Cardiovascular Disease in the Elderly

Cardiovascular Disease in the Elderly

FUNDAMENTAL AND CLINICAL CARDIOLOGY

Editor-in-Chief Samuel Z. Goldhaber, M.D. Harvard Medical School and Brigham and Women’s Hospital Boston, Massachusetts, U.S.A.

1. Drug Treatment of Hyperlipidemia, edited by Basil M. Rifkind 2. Cardiotonic Drugs: A Clinical Review, Second Edition, Revised and Expanded, edited by Carl V. Leier 3. Complications of Coronary Angioplasty, edited by Alexander J. R. Black, H. Vernon Anderson, and Stephen G. Ellis 4. Unstable Angina, edited by John D. Rutherford 5. Beta-Blockers and Cardiac Arrhythmias, edited by Prakash C. Deedwania 6. Exercise and the Heart in Health and Disease, edited by Roy J. Shephard and Henry S. Miller, Jr. 7. Cardiopulmonary Physiology in Critical Care, edited by Steven M. Scharf 8. Atherosclerotic Cardiovascular Disease, Hemostasis, and Endothelial Function, edited by Robert Boyer Francis, Jr. 9. Coronary Heart Disease Prevention, edited by Frank G. Yanowitz 10. Thrombolysis and Adjunctive Therapy for Acute Myocardial Infarction, edited by Eric R. Bates 11. Stunned Myocardium: Properties, Mechanisms, and Clinical Manifestations, edited by Robert A. Kloner and Karin Przyklenk 12. Prevention of Venous Thromboembolism, edited by Samuel Z. Goldhaber 13. Silent Myocardial Ischemia and Infarction: Third Edition, Peter F. Cohn 14. Congestive Cardiac Failure: Pathophysiology and Treatment, edited by David B. Barnett, Hubert Pouleur and Gary S. Francis 15. Heart Failure: Basic Science and Clinical Aspects, edited by Judith K. Gwathmey, G. Maurice Briggs, and Paul D. Allen 16. Coronary Thrombolysis in Perspective: Principles Underlying Conjunctive and Adjunctive Therapy, edited by Burton E. Sobel and Desire Collen 17. Cardiovascular Disease in the Elderly Patient, edited by Donald D. Tresch and Wilbert S. Aronow 18. Systemic Cardiac Embolism, edited by Michael D. Ezekowitz 19. Low-Molecular-Weight Heparins in Prophylaxis and Therapy of Thromboembolic Diseases, edited by Henri Bounameaux 20. Valvular Heart Diseases, edited by Muayed Al Zaibag and Carlos M. G. Duran 21. Implantable Cardioverter-Defibrillators: A Comprehensive Textbook, edited by N. A. Mark Estes, Antonis S. Manolis, and Paul J. Wang 22. Individualized Therapy of Hypertension, edited by Norman M. Kaplan and C. Venkata S. Ram

23. Atlas of Coronary Balloon Angioplasty, Bernhard Meier and Vivek K. Mehan 24. Lowering Cholesterol in High-Risk Individuals and Populations, edited by Basil M. Rifkind 25. Interventional Cardiology: New Techniques and Strategies for Diagnosis and Treatment, edited by Christopher J. White and Stephen Ramee 26. Molecular Genetics and Gene Therapy of Cardiovascular Diseases, edited by Stephen C. Mockrin 27. The Pericardium: A Comprehensive Textbook, David H. Spodick 28. Coronary Restenosis: From Genetics to Therapeutics, edited by Giora Z. Feuerstein 29. The Endothelium in Clinical Practice: Source and Target of Novel Therapies, edited by Gabor M. Rubanyi and Victor J. Dzau 30. Molecular Biology of Cardiovascular Disease, edited by Andrew R. Marks and Mark B. Taubman 31. Practical Critical Care in Cardiology, edited by Zab Mohsenifar and P. K. Shah 32. Intravascular Ultrasound Imaging in Coronary Artery Disease, edited by Robert J. Siegel 33. Saphenous Vein Bypass Graft Disease, edited by Eric R. Bates and David R. Holmes, Jr. 34. Exercise and the Heart in Health and Disease: Second Edition, Revised and Expanded, edited by Roy J. Shephard and Henry S. Miller, Jr 35. Cardiovascular Drug Development: Protocol Design and Methodology, edited by Jeffrey S. Borer and John C. Somberg 36. Cardiovascular Disease in the Elderly Patient: Second Edition, Revised and Expanded, edited by Donald D. Tresch and Wilbert S. Aronow 37. Clinical Neurocardiology, Louis R. Caplan, J. Willis Hurst, and Mark Chimowitz 38. Cardiac Rehabilitation: A Guide to Practice in the 21st Century, edited by Nanette K. Wenger, L. Kent Smith, Erika Sivarajan Froelicher, and Patricia McCall Comoss 39. Heparin-Induced Thrombocytopenia, edited by Theodore E. Warkentin and Andreas Greinacher 40. Silent Myocardial Ischemia and Infarction: Fourth Edition, Peter F. Cohn 41. Foundations of Cardiac Arrhythmias: Basic Concepts and Clinical Approaches, edited by Peter M. Spooner and Michael R. Rosen 42. Interpreting Electrocardiograms: Using Basic Principles and Vector Concepts, J. Willis Hurst 43. Heparin-Induced Thrombocytopenia: Second Edition, edited by Theodore E. Warkentin and Andreas Greinacher 44. Thrombosis and Thromboembolism, edited by Samuel Z. Goldhaber and Paul M. Ridker 45. Cardiovascular Plaque Rupture, edited by David L. Brown 46. New Therapeutic Agents in Thrombosis and Thrombolysis: Second Edition, Revised and Expanded, edited by Arthur A. Sasahara and Joseph Loscalzo 47. Heparin-Induced Thrombocytopenia: Third Edition, edited by Theodore E. Warkentin and Andreas Greinacher 48. Cardiovascular Disease in the Elderly, Third Edition, edited by Wilbert Aronow and Jerome Fleg 49. Atrial Fibrillation, edited by Peter Kowey and Gerald Naccarelli

50. Heart Failure: A Comprehensive Guide to Diagnosis and Treatment, edited by G. William Dec 51. Pharmacoinvasive Therapy in Acute Myocardial Infarction, edited by Harold L. Dauerman and Burton E. Sobel 52. Clinical, Interventional, and Investigational Thrombocardiology, edited by Richard Becker and Robert A. Harrington 53. Pediatric Heart Failure, Robert Shaddy and Gil Wernovsky 54. Cardiac Remodeling: Mechanisms and Treatment, edited by Barry Greenberg 55. Acute Coronary Syndromes, Third Edition, edited by Eric Topol 56. Treatment of Advanced Heart Disease, edited by Kenneth L. Baughman and William A. Baumgartner 57. Prevention of High-Risk Cardiovascular Disease, edited by Antonio Gotto and Peter P. Toth 58. Obesity and Cardiovascular Disease, edited by Malcolm K. Robinson and Abraham Thomas 59. Risk Factors in Coronary Artery Disease, edited by P. K. Shah 60. Handbook of Cardiovascular Magnetic Resonance Imaging, edited by Gerald M. Pohost and Krishna S. Nayak 61. Acute Aortic Disease, edited by John A. Elefteriades 62. Heparin-Induced Thrombocytopenia, Fourth Edition, edited by Theodore E. Warkentin and Andreas Greinacher 63. Cardiovascular Disease in the Elderly, Fourth Edition, edited by Wilbert S. Aronow, Jerome L. Fleg, and Michael W. Rich 64. Reperfusion Therapy for Acute Myocardial Infarction, edited by Eric R. Bates

Cardiovascular Disease in the Elderly Fourth Edition

Edited by

Wilbert S. Aronow

New York Medical College Department of Medicine Valhalla, New York, USA

Jerome L. Fleg

National Institutes of Health Bethesda, Maryland, USA

Michael W. Rich

Washington University St. Louis, Missouri, USA

Informa Healthcare USA, Inc. 52 Vanderbilt Avenue New York, NY 10017 # 2008 by Informa Healthcare USA, Inc. Informa Healthcare is an Informa business No claim to original U.S. Government works Printed in the United States of America on acid-free paper 10 9 8 7 6 5 4 3 2 1 International Standard Book Number-10: 1-4200-6170-4 (Hardcover) International Standard Book Number-13: 978-1-4200-6170-3 (Hardcover) This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and sources are indicated. A wide variety of references are listed. Reasonable efforts have been made to publish reliable data and information, but the author and the publisher cannot assume responsibility for the validity of all materials or for the consequence of their use. No part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission from the publishers. For permission to photocopy or use material electronically from this work, please access www.copyright.com (http://www.copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC) 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. CCC is a not-for-profit organization that provides licenses and registration for a variety of users. For organizations that have been granted a photocopy license by the CCC, a separate system of payment has been arranged. Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. Library of Congress Cataloging-in-Publication Data Cardiovascular disease in the elderly / edited by Wilbert S. Aronow, Jerome L. Fleg, Michael W. Rich. — 4th ed. p. ; cm. — (Fundamental and clinical cardiology ; v. 63) Includes bibliographical references and index. ISBN-13: 978-1-4200-6170-3 (hb : alk. paper) ISBN-10: 1-4200-6170-4 (hb : alk. paper) 1. Geriatric cardiology. I. Aronow, Wilbert S. II. Fleg, Jerome L. III. Rich, Michael W. IV. Series. [DNLM: 1. Cardiovascular Diseases. 2. Aged. 3. Cardiovascular Diseases—physiopathology. W1 FU538TD v.63 2008 / WG 100 C26728 2008] RC669.C279 2008 618.970 612—dc22 2007042246 For Corporate Sales and Reprint Permissions call 212-520-2700 or write to: Sales Department, 52 Vanderbilt Avenue, 16th floor, New York, NY 10017. Visit the Informa Web site at www.informa.com and the Informa Healthcare Web site at www.informahealthcare.com

Series Introduction

Informa Healthcare has developed various series of beautifully produced books in different branches of medicine. These series have facilitated the integration of rapidly advancing information for both the clinical specialist and the researcher. Wilbert S. Aronow, with coeditors Jerome L. Fleg and Michael W. Rich, has completely rewritten and updated the best-selling textbook Cardiovascular Disease in the Elderly. With the graying of our population, the fourth edition of this informative and comprehensive book becomes more important than ever before. The elderly require a special approach that includes a profound knowledge of geriatric epidemiology with regard to diagnosis, therapy, and preventive effort. I know that from my own clinical practice of cardiovascular medicine, as two of my patients celebrated their 100th birthdays this year. The eight sections of this text are logically laid out, beginning with aging changes and focusing next on coronary disease, valvular heart disease, cardiomyopathy, and electrophysiology. The rest of this magnificent book covers cerebrovascular disease and miscellaneous but crucial topics such as quality of life in older patients with cardiovascular disease. This multiauthored text remains cohesive because the editors are also coauthors of multiple chapters in each section of the book. My goal as editor-in-chief of the Fundamental and Clinical Cardiology Series is to assemble the talents of world-renowned authorities to discuss virtually every area of cardiovascular medicine. I feel we have achieved this objective with Cardiovascular Disease in the Elderly, Fourth Edition. Future contributions to this series will include books on molecular biology, interventional cardiology, and clinical management of such problems as coronary artery disease, venous thromboembolism, peripheral vascular disease, and cardiac arrhythmias. Samuel Z. Goldhaber, M.D. Harvard Medical School Brigham and Women’s Hospital Boston, Massachusetts, U.S.A. Editor-in-Chief Fundamental and Clinical Cardiology Series

iii

Foreword

It should come as no surprise to any physician practicing medicine in an industrialized nation in the early years of the 21st century that the demography of the patient population has changed dramatically over the last three or four decades. Indeed, that there is a remarkable “graying” trend for both in- and outpatients in our society is an acknowledged fact immediately recognized by contemporary medical students, residents, subspecialty fellows, and practicing clinicians. In my own cardiology and internal medicine practice, more than half of the individuals that I treat fall into the geriatric category with their special needs, requirements, and problems. A simple clinical example demonstrates these issues exquisitely: An 85-year-old patient has symptomatic, critical aortic stenosis. Should this patient undergo life-prolonging aortic valve replacement surgery, and would such surgery represent “appropriate care” for this 85-year-old person? The answer to this question, of course, depends on many factors, not just the patient’s age and diagnosis. For example, what is the functional status, physically and mentally, of our 85-year-old patient? What comorbid conditions affect this individual? Finally, what does this patient want to do after the attendant risk and discomfort of the aortic valve operation have been described? This clinical scenario is one that I face literally every week, and I suspect that most clinicians in our society do as well. I doubt that any cardiologist would disagree with a recommendation for “no surgery” if the described patient had severe advanced Alzheimer’s disease and was confined to a nursing home bed. On the other hand, if the patient were living independently and were vigorous and active, I suspect that just about every cardiologist would agree that this patient should undergo AVR if the patient agreed to the risk of mortal and morbid events associated with the operation. The two extremes just described are rather straightforward; however, a large number of patients fall between the limits of these two examples. For this intermediate group of patients, the negotiation with the patients and their families can be complex, requiring special knowledge on the part of the practitioner. That is exactly the kind of information that is contained in this superb text, with its extensive compilation of geriatric cardiovascular topics. Building on several previous strong editions, the current book is authoritative, up to date, and well organized. Each chapter has been written by an acknowledged authority in the field of geriatric cardiology. This book should be required reading for every practicing cardiologist and every cardiology fellow currently in training. Every modern clinician working today must face the reality of our changing population demographics: A tsunami of older patients has already been sighted, and it is v

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Foreword

rapidly approaching our clinical coastline! These individuals will require special attention based on a thorough knowledge of the diagnostic and therapeutic strategies that differ in many ways from those of younger patients. The present text will enable physicians involved in the care of these elderly individuals to deliver quality, compassionate, and empathetic care to these patients, almost all of whom will have clinically important cardiovascular disease. I recommend this important text to every physician who will have to deal with this burgeoning population of elderly individuals. As clinicians involved in the care of these geriatric patients, it is our professional responsibility to give them the very best health care possible. This book will help us do just that. Joseph Alpert University of Arizona, College of Medicine Tucson, Arizona, U.S.A.

Preface to the Fourth Edition

In 2010, the first of the “baby boomers” will turn 65 years old. This event will herald an explosive growth in the older adult population in the United States, from just over 40 million in 2010 to approximately 72 million by 2030, an increase of 80%a. Concomitantly, the proportion of the populace over age 65 will increase from about 1 in 8 to about 1 in 5. Accompanying this “graying of America” will be a dramatic rise in the number of older persons with clinically manifest—or at risk of developing—cardiovascular disorders, including hypertension, coronary artery disease, valvular heart disease, heart failure, and cardiac rhythm disturbances. Since persons over 65 already account for more than 80% of all deaths attributable to cardiovascular disease, it will become imperative in the years ahead for all clinicians involved in the care of older adults—not just primary care physicians, geriatricians, and cardiologists, but also surgeons, anesthesiologists, other medical subspecialists, and nurse practitioners—to have a basic understanding of the effects of aging on cardiovascular structure and function, as well as of the impact of aging and prevalent comorbid conditions on the clinical presentation, diagnosis, and response to therapy in older adults with cardiovascular disease. As with prior editions, the primary objective of the present volume is to provide an upto-date and in-depth, yet clinically relevant and “readable,” overview of the epidemiology, pathophysiology, evaluation, and treatment of cardiovascular disorders in older adults. All chapters have been thoroughly updated by recognized experts to incorporate the most recent developments in the field. To the extent possible, clinical recommendations are “evidence based,” but it is also acknowledged that existing data are often thin to nonexistent in the very elderly (persons 85 years of age or older), and especially in older adults with multiple coexisting conditions and/or frailty. Thus, careful consideration of each patient’s unique clinical and psychosocial circumstances, medical and nonmedical needs, and personal preferences is required in designing an individualized management plan. Indeed, it is perhaps in the compassionate management of these challenging patients where the “art of medicine” most clearly flourishes. The first three editions of Cardiovascular Disease in the Elderly were published by Marcel Dekker in 1994, 1999, and 2004; i.e., at five-year intervals. With the fourth edition, Informa Healthcare has taken over as publisher, and publication has been accelerated by a year, primarily in response to the increasing volume of literature relevant to cardiovascular disease in older adults. It is noteworthy that the number of articles a

U.S. Census Bureau. U.S. Interim Projections by Age, Sex, Race, and Hispanic Origin. Available at: www. census.gov/ipc/www/usinterimproj. Accessed November 26, 2006.

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Preface to the Fourth Edition

posted on Medline at the intersection of “cardiovascular disease” and “age greater than 65 years” increased from 1391 for the three-year period 1997–1999 to 1842 for the period 2000–2002, and to 2630 in the interval 2003–2005—a doubling in the number of citations over a nine-year period. In further recognition of the growing importance of the elderly population in cardiovascular medicine, an increasing number of clinical trials focusing on older adults have been undertaken, and practice guidelines are increasingly providing explicit commentary on the diagnosis and management of older adults. With this edition, Dr. Michael W. Rich joins Drs. Wilbert S. Aronow and Jerome L. Fleg as coeditor. The general format of the text is similar to the previous edition. There are eight sections comprising 32 chapters, all written by recognized authorities in geriatric cardiology. The chapter topics remain the same as those in the third edition, with one exception. Information from the chapter “Pathophysiology of Coronary Artery Disease in the Elderly” has been incorporated into the other chapters on the diagnosis and treatment of this condition, while a new chapter, “Disability and Frailty in Older Patients with Cardiovascular Disease,” has been added. We would like to thank all of the contributors for their outstanding work. We also wish to express our gratitude to Sandra Beberman at Informa Healthcare for her dedication and support in bringing this fourth edition to fruition. Finally, we want to thank you, the reader, for your commitment to providing the best possible care for your older patients with cardiovascular disease. We hope you will find this volume to be a valuable resource as you strive to help your older patients enjoy both longer and fuller lives. We welcome any comments you may have. Wilbert S. Aronow Jerome L. Fleg Michael W. Rich

Contents

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PART I: AGING CHANGES IN THE CARDIOVASCULAR SYSTEM 1.

Normal Aging of the Cardiovascular System Jerome L. Fleg and Edward G. Lakatta

.....................

2.

Echocardiographic Measurements in Elderly Patients Without Clinical Heart Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Julius M. Gardin and Cheryl K. Nordstrom

1

45

3.

Morphological Features of the Elderly Heart William C. Roberts

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75

4.

Cardiovascular Drug Therapy in the Elderly .................. . William H. Frishman, Wilbert S. Aronow, and Angela Cheng-Lai

99

PART II: CORONARY ARTERY DISEASE: RISK FACTORS AND EPIDEMIOLOGY 5.

Systemic Hypertension in the Elderly William H. Frishman

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137

6.

Disorders of Lipid Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Joseph E. Thomas and JoAnne M. Foody

159

7.

Diabetes Mellitus and Cardiovascular Disease in the Elderly Gabriel Gregoratos and Gordon Leung

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179

8.

Epidemiology of Coronary Heart Disease in the Elderly Pantel S. Vokonas and William B. Kannel

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215

ix

x

Contents

PART III: CORONARY ARTERY DISEASE ............ .

243

10.

Angina in the Elderly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Wilbert S. Aronow and William H. Frishman

269

11.

Therapy of Acute Myocardial Infarction Michael W. Rich

293

12.

Management of the Older Patient After Myocardial Infarction Wilbert S. Aronow

13.

Surgical Management of Coronary Artery Disease in the Elderly Edward A. Stemmer and Wilbert S. Aronow

14.

Percutaneous Coronary Intervention in the Elderly David R. Holmes Jr. and Mandeep Singh

15.

9.

Diagnosis of Coronary Heart Disease in the Elderly Wilbert S. Aronow and Jerome L. Fleg

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327

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351

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387

Exercise Training and Cardiac Rehabilitation in Older Cardiac Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Philip A. Ades

405

PART IV: VALVULAR HEART DISEASE 16.

Aortic Valve Disease in the Elderly . . . . . . . . . . . . . . . . . . . . . . . . . . Wilbert S. Aronow and Melvin B. Weiss

17.

Mitral Regurgitation, Mitral Stenosis, and Mitral Annular Calcification in the Elderly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Melvin D. Cheitlin and Wilbert S. Aronow

18.

Infective Endocarditis in the Elderly . . . . . . . . . . . . . . . . . . . . . . . . . Thomas C. Cesario and David A. Cesario

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445 481

PART V: CARDIOMYOPATHIES AND HEART FAILURE 19.

Cardiomyopathies in the Elderly . . . . . . . . . . . . . . . . . . . . . . . . . . . . John A. McClung, Michele Nanna, and Wilbert S. Aronow

493

20.

Thyroid Heart Disease in the Elderly Myron Miller and Steven R. Gambert

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517

21.

Heart Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Dalane W. Kitzman and Jerome L. Fleg

541

Contents

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PART VI: ARRHYTHMIAS AND CONDUCTION DISORDERS ............. .

577

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605

22.

Supraventricular Tachyarrhythmias in the Elderly Wilbert S. Aronow and Carmine Sorbera

23.

Ventricular Arrhythmias in the Elderly Wilbert S. Aronow and Carmine Sorbera

24.

Bradyarrhythmias and Cardiac Pacemakers in the Elderly Anthony D. Mercando

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627

PART VII: CEREBROVASCULAR DISEASE 25.

Cerebrovascular Disease in the Elderly Patient Jesse Weinberger

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645

26.

Evaluation of Syncope in the Elderly Patient . . . . . . . . . . . . . . . . . . . Karen M. Stugensky, Gerald W. Neuberg, and Mathew S. Maurer

673

PART VIII: MISCELLANEOUS TOPICS 27.

Anticoagulation in the Elderly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Laurie G. Jacobs and Henny H. Billett

705

28.

Acute Pulmonary Embolism in the Elderly Paul D. Stein

731

29.

Management of Peripheral Arterial Disease in the Elderly Wilbert S. Aronow

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749

30.

Perioperative Cardiovascular Evaluation and Treatment of Elderly Patients Undergoing Noncardiac Surgery . . . . . . . . . . . . . Colleen Christmas, Roy C. Ziegelstein, and Lee A. Fleisher

769

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31.

Disability and Frailty in Older Patients with Cardiovascular Disease John E. Morley and Michael W. Rich

32.

Ethical Decisions and End-of-Life Care in Older Patients with Cardiovascular Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lofty L. Basta and Henry D. McIntosh

819

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831

Index

Contributors

Philip A. Ades Fletcher-Allen Health Care, University of Vermont College of Medicine, Burlington, Vermont, U.S.A. Wilbert S. Aronow Divisions of Cardiology, Geriatrics, and Pulmonary/Critical Care, Department of Medicine, New York Medical College, Valhalla, New York, U.S.A. Lofty L. Basta

University of South Florida, Tampa, Florida, U.S.A.

Henny H. Billett Division of Hematology, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York, U.S.A. Thomas C. Cesario David A. Cesario

University of California, Irvine, California, U.S.A. University of California, Irvine, California, U.S.A.

Melvin D. Cheitlin

University of California, San Francisco, California, U.S.A.

Angela Cheng-Lai New York, U.S.A.

Department of Pharmacy, Montefiore Medical Center, Bronx,

Colleen Christmas Johns Hopkins Bayview Medical Center, Johns Hopkins University, Baltimore, Maryland, U.S.A. Jerome L. Fleg Division of Cardiovascular Diseases, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, U.S.A. Lee A. Fleisher Department of Anesthesiology and Critical Care, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, U.S.A. JoAnne M. Foody Yale University School of Medicine, New Haven, Connecticut, U.S.A. William H. Frishman Department of Medicine, New York Medical College/ Westchester Medical Center, Valhalla, New York, U.S.A.

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Contributors

Steven R. Gambert Sinai Hospital of Baltimore and the Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, U.S.A. Julius M. Gardin St. John Hospital and Medical Center and Wayne State University, Detroit, Michigan, U.S.A. Gabriel Gregoratos David R. Holmes Jr. Minnesota, U.S.A.

University of California, San Francisco, California, U.S.A. Mayo Clinic College of Medicine, Mayo Clinic, Rochester,

Laurie G. Jacobs Division of Geriatrics, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York, U.S.A. William B. Kannel Framingham Heart Study, Boston University School of Medicine, Boston, Massachusetts, U.S.A. Dalane W. Kitzman Wake Forest University School of Medicine, Winston-Salem, North Carolina, U.S.A. Edward G. Lakatta Gordon Leung

National Institute on Aging, Bethesda, Maryland, U.S.A.

University of California, San Francisco, California, U.S.A.

Mathew S. Maurer Cardiology and Division of Geriatric Medicine and Aging, Columbia University, New York Presbyterian Hospital, New York, New York, U.S.A. John A. McClung Department of Medicine, Division of Cardiology, New York Medical College/Westchester Medical Center, Valhalla, New York, U.S.A. Henry D. McIntosh

Baylor College of Medicine, Houston, Texas, U.S.A.

Anthony D. Mercando Columbia University College of Physicians and Surgeons, New York, and Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York, U.S.A. Myron Miller Sinai Hospital of Baltimore and the Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, U.S.A. John E. Morley Division of Geriatric Medicine, Saint Louis University School of Medicine and Geriatric Research Education and Clinical Center (GRECC), Veterans Affairs Medical Center, St. Louis, Missouri, U.S.A. Michele Nanna Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, U.S.A. Gerald W. Neuberg Department of Medicine, Division of Cardiology, Columbia University, New York Presbyterian Hospital, New York, New York, U.S.A.

Contributors

xv

Cheryl K. Nordstrom Michael W. Rich U.S.A.

University of Michigan, Ann Arbor, Michigan, U.S.A.

Washington University School of Medicine, St. Louis, Missouri,

William C. Roberts Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, Texas, U.S.A. Mandeep Singh U.S.A.

Mayo Clinic College of Medicine, Mayo Clinic, Rochester, Minnesota,

Carmine Sorbera Department of Medicine, Division of Cardiology, New York Medical College/Westchester Medical Center, Valhalla, New York, U.S.A. Paul D. Stein

St. Joseph Mercy Oakland, Pontiac, Michigan, U.S.A.

Edward A. Stemmer University of California at Irvine School of Medicine and Veterans Affairs Medical Center, Long Beach, California, U.S.A. Karen M. Stugensky Department of Medicine, Division of Cardiology, Columbia University, New York Presbyterian Hospital, New York, New York, U.S.A. Joseph E. Thomas Yale University School of Medicine, New Haven, Connecticut, U.S.A. Pantel S. Vokonas VA Normative Aging Study, VA Boston Healthcare System, Boston University School of Medicine, Boston, Massachusetts, U.S.A. Jesse Weinberger Department of Neurology, Mount Sinai School of Medicine, New York, New York, U.S.A. Melvin B. Weiss Department of Medicine, Division of Cardiology, New York Medical College/Westchester Medical Center, Valhalla, New York, U.S.A. Roy C. Ziegelstein Johns Hopkins Bayview Medical Center, Johns Hopkins University, Baltimore, Maryland, U.S.A.

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Normal Aging of the Cardiovascular System Jerome L. Fleg Division of Cardiovascular Diseases, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, U.S.A.

Edward G. Lakatta National Institute on Aging, Bethesda, Maryland, U.S.A.

INTRODUCTION Since 1900, the average life expectancy for Americans has risen from 48 to 77.3 years. Over this period, the U.S. population expanded threefold, while the subset aged 65 and older increased 10-fold. The post–World War II baby boom will further expand this age group from the current 13% to 19.6% in 2030 (1). Furthermore, the fastest-growing age group, comprising those aged 85 years or older, has quadrupled since 1960 and will reach 19.5 million by 2030 (Fig. 1). Because both the prevalence and incidence of cardiovascular (CV) disease increase dramatically with age, this “graying” of the population has created a huge number of elderly patients requiring treatment. It must be emphasized, however, that aging per se is not necessarily accompanied by CV disease. This chapter will set the stage for those that follow by delineating the changes in the CV system that occur during the aging process in the absence of CV disease. This is a challenging task, given the many factors that blur their separation. Nevertheless, it is important to define normal CV structure and function in older adults to facilitate the accurate diagnosis of CV disease in this rapidly growing age group. An additional theme of this chapter will be to indicate how aging changes in the CV system may themselves predispose to the development of CV disease. The enhanced CV risk associated with age indicates important interactions between mechanisms that underlie aging and those that underlie diseases. The nature of these interactions is complex and involves not only mechanisms of aging but also multiple defined and undefined (e.g., genetic) risk factors. The role of specific age-associated changes in CV structure and function has been, and largely continues to be, unrecognized by those who shape medical policy. Yet quantitative information on age-associated alterations in CV structure and function is essential to define and target the specific characteristics of CV aging that render it such a major risk factor.

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Figure 1 Projected growth of the elderly population in the United States, stratified by age group. Source: From Ref. 1

Such information is also required to differentiate between the limitations of an elderly person that relate to disease and those that are within expected normal limits. METHODOLOGICAL ISSUES Numerous methodological issues must be addressed in attempting to define “normal” aging. Because the population sample from which norms are derived will strongly influence the results obtained, it should be representative of the general population. For example, neither a seniors running club nor nursing home residents would yield an appropriate estimate of maximal exercise capacity that could be applied to the majority of elders. Additionally, the degree of screening used to define a normal population can profoundly influence the results. In clinically healthy older adults, a resting electrocardiogram (ECG), echocardiogram, or exercise perfusion imaging study will often identify silent CV disease, especially coronary artery disease (CAD). If several such screening tests are used, only a small proportion of the older population may qualify as normal, limiting the applicability of findings to the majority of elderly individuals. Furthermore, the inclusion limits chosen for body fatness, blood pressure, smoking status, and other constitutional or lifestyle variables will significantly influence the normal values for measuring CV variables. For example, if a systolic pressure of
140 mmHg is considered hypertension, and if hypertension is considered a disease, then individuals with a systolic pressure between 140 and 160 mmHg, who a decade ago were thought to be normotensive, are now identified as having CV disease. Numerous studies have shown that individuals who manifest even modest elevations in systolic and pulse pressures are more likely to develop clinical disease or die from it. Additional methodological factors can affect the definitions of normal aging. Crosssectional studies, which study individuals across a wide age range at one time point, may underestimate the magnitude of age-associated changes because, in such studies, older normal persons represent “survival of the fittest.” True age-induced changes are better estimated by longitudinal studies, in which given individuals are examined serially over time. A reality of aging research, however, is that most data are derived from cross-sectional studies because they are easier to perform. Even longitudinal studies have their limitations— changes in methodology or measurement drift over time and development of disease in

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previously healthy persons. Finally, secular trends such as the downward drift in serum cholesterol or increasing obesity of Americans can alter age-related longitudinal changes. In the current chapter, emphasis will be given to data obtained from communitydwelling samples screened for the absence of clinical, and in some cases subclinical, CV disease and major systemic disorders. A sizable portion of the data presented derives from the authors’ studies over the past three decades in community-based volunteers from the Baltimore Longitudinal Study of Aging (BLSA). UNSUCCESSFUL VASCULAR AGING AS THE ‘‘RISKY’’ COMPONENT OF AGING Intimal Medial Thickening Aging changes in the arterial tree of individuals who are considered healthy may have relevance to the exponential age-associated increase in CV disease. Cross-sectional studies in humans have found that wall thickening and dilatation are prominent structural changes that occur within large elastic arteries during aging (2). Postmortem studies indicate that aortic wall thickening with aging consists mainly of intimal thickening, even in populations with a low incidence of atherosclerosis (3). Noninvasive measurements made within the context of several epidemiological studies indicate that the carotid wall intimal medial (IM) thickness increases nearly threefold between 20 and 90 years of age, which is also the case in BLSA individuals rigorously screened to exclude carotid or coronary arterial disease (Fig. 2, top panel). Some investigators believe that the age-associated increase in IM thickness in humans represents an early stage of atherosclerosis (4). Indeed, excessive IM thickening at a given age predicts silent CAD (4). Since silent CAD often progresses to clinical CAD, it is not surprising that increased IM thickness (a vascular endpoint) predicts future clinical CV disease. A plethora of other epidemiological studies of individuals not initially screened to exclude the presence of occult CV disease have indicated that increased IM thickness is an independent predictor of future CV events. Note in Figure 2 (bottom panel) that the degree of risk varies with the degree of vascular thickening and that the risk gradation among quintiles of IM thickening is nonlinear, with the greatest risk occurring in the upper quintile (5). Thus, those older persons in the upper quintile of IM thickness may be considered to have aged “unsuccessfully” or to have “subclinical” vascular disease. The potency of IM thickness as a risk factor in older individuals equals or exceeds that of most other, more “traditional,” risk factors. Age-dependent IM thickening has been noted in the absence of atherosclerosis, both in laboratory animals and in humans (3). Thus, the “subclinical disease” of excessive IM thickening is not necessarily “early” atherosclerosis. Rather, “subclinical disease” is strongly correlated with arterial aging. Interpreted in this way, the increase in IM thickness with aging is analogous to the intimal hyperplasia that develops in aortocoronary saphenous vein grafts, which is independent of atherosclerosis, but predisposes for its later development (6). Age-associated endothelial dysfunction, arterial stiffening, and arterial pulse pressure widening can also be interpreted in the same way. Combinations of these processes occurring to varying degrees determine the overall vascular aging profile of a given individual (i.e., the degree of “unsuccessful” vascular aging). It is currently believed that additional risk factors (e.g., hypertension, smoking, dyslipidemia, diabetes, diet, or yet unidentified genetic factors) are required to interact with vascular aging (as described above) to activate a preexisting atherosclerotic plaque. According to this view, atherosclerosis that increases with aging is not a specific disease,

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Figure 2 (Top) The common carotid intimal-medial thickness in healthy BLSA volunteers as a function of age. (Bottom) Common carotid intimal-medial thickness predicts future cardiovascular events in the Cardiovascular Health Study. Abbreviation: BLSA, Baltimore Longitudinal Study of Aging. Source: (Top) From Ref. 4 and (Bottom) From Ref. 5.

but an interaction between atherosclerotic plaque and intrinsic features related to vascular aging modulated by atherosclerotic risk factors. Evidence in support of this view comes from studies in which an atherogenic diet caused markedly more severe atherosclerotic lesions in older versus younger rabbits and nonhuman primates despite similar elevations of serum lipids (7,8). Hence, it is possible that atherosclerosis occurring at younger ages may be attributable not only to exaggerated traditional CV risk factors but also to accelerated aging of the vascular wall. Of course, the traditional risk factors may

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themselves accelerate aging of the vascular wall. Studies in various populations with clinically defined vascular disease have demonstrated that pharmacological and lifestyle (diet, physical activity) interventions can retard the progression of IM thickening (9–14). Endothelial Dysfunction The endothelial monolayer that lines the luminal surface of the vascular tree plays a pivotal role in regulating multiple arterial properties, including vessel tone, permeability, response to inflammation, and angiogenesis. Several of these functions undergo important age-associated alterations. Endothelium-derived mediators such as nitric oxide (NO) and endothelin-1 are determinants of arterial tone and compliance, suggesting that endothelial cells may modulate arterial stiffness. Brachial arterial flow mediated dilation, mediated in large part by NO, declines with age in both sexes, even in the absence of other CV risk factors (15). A decline of *75% in this flow-mediated vasodilation occurs in men between ages 40 and 70 years (Fig. 3). This decline begins approximately a decade later in women, perhaps because of the protective effect of estrogen, but is nearly 2.5 times as steep compared with men (15). The impairment of endothelial-mediated vasodilatation with aging in humans can be partially reversed by L-arginine administration, suggesting that NO production becomes reduced with aging (16). Plasma levels of asymmetric dimethyl arginine, which reduces nitric oxide synthase (NOS) activity, also increase with age in humans (16). The effect of age on endothelial function in central arteries, however,

Figure 3 Age-associated decline in enthothelially mediated vasodilation in healthy volunteers. Note that the decline begins about a decade later in women than men, perhaps due to the protective effects of estrogen on endothelial function. Source: From Ref. 15.

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has not been directly assessed in humans without clinical disease. In contrast to endothelium-mediated vasodilation, the vasodilator response to sublingual nitroglycerin is unrelated to age (15). Several CV risk factors and disorders are associated with endothelial dysfunction, including hypertension, hypercholesterolemia, insulin resistance, cigarette smoking, CAD, and heart failure. Furthermore, impaired endothelial vasoreactivity, in both the coronary and peripheral arterial beds, is an independent predictor of future CV events (17,18). Hypertensive individuals exhibit endothelial dysfunction (19,20), and the mechanisms underlying their endothelial dysfunction are similar to those that occur with normotensive aging, albeit they appear at an earlier age (20). The normotensive offspring of hypertensives also exhibit endothelial dysfunction (21), suggesting that endothelial dysfunction may precede the development of clinical hypertension. Age-associated endothelial dysfunction, arterial stiffening, and IM thickening are risk factors for arterial diseases, even after accounting for other risk factors, such as arterial pressure, plasma lipids, smoking, etc. The interaction between arterial wall stiffening and CV diseases may set in motion a vicious cycle. In this cycle, alterations in the mechanical properties of the vessel wall contribute to endothelial cell dysfunction and, ultimately, to arterial stiffening. Arterial Stiffness and Compliance The increase in arterial wall thickening and reduction in endothelial function with advancing age are accompanied by an increase in arterial stiffening and a reduction in compliance. Age-associated structural changes in the arterial media that increase vascular stiffness include increased collagen content, covalent cross-linking of the collagen, reduced elastin content, elastin fracture, and calcification (22,23). Strictly speaking, stiffness and its inverse, distensibility, depend on intrinsic structural properties of the blood vessel wall that relate pressure change with a corresponding change in volume. Pulse Wave Velocity Each systolic contraction of the ventricle generates a pressure wave that propagates centrifugally down the arterial tree, slightly preceding the luminal flow wave generated during systole. The propagation velocity of this wave is proportional to the stiffness of the arterial wall. The velocity of the pulse wave in vivo is determined not only by the intrinsic stress/strain relationship (stiffness) of the vascular wall, but also by the smooth muscle tone, which is reflected by the mean arterial pressure. Noninvasive measures of the velocity of this pulse wave allow for large-scale epidemiological studies to examine its determinants and prognostic importance. In both rigorously screened normal subjects (24) and populations with varying prevalence of CV disease (25–27), a significant age-associated increase in pulse wave velocity (PWV) has been observed in men and women (Fig. 4A). In contrast to central arteries, the stiffness of muscular arteries does not increase with advancing age (28). Thus, the manifestations of arterial aging may vary among the different vascular beds, reflecting differences in the structural compositions of the arteries and, possibly, differences in the age-associated signaling cascades that modulate the arterial properties, or differences in the response to these signals across the arterial tree. Increased PWV has traditionally been linked to structural alterations in the vascular media, such as those observed with aging. Prominent age-associated increases in PWV have been demonstrated in populations with little or no atherosclerosis, again

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Figure 4 Scatterplots of aortofemoral pulse wave velocity (Panel A), and carotid artery augmentation index (Panel B) as a function of age in healthy non-endurance trained BLSA volunteers. A similar ageassociated increase in both measures of arterial stiffness was seen in men and women. Abbreviation: BLSA, Baltimore Longitudinal Study of Aging. Source: Adapted from Ref. 24.

indicating that these vascular parameters are not necessarily indicative of atherosclerosis (29). However, more recent data emerging from epidemiological studies indicate that increased large vessel stiffening also occurs in the context of atherosclerosis (30,31), metabolic syndrome (32), and diabetes (33,34). The link may be that stiffness is governed not only by the structural changes within the matrix, as noted above, but also by endothelial regulation of vascular smooth muscle tone and other aspects of vascular wall structure/function. Thus, there is evidence of a vicious cycle: altered mechanical properties of the vessel wall facilitate the development of atherosclerosis, which in turn increases arterial stiffness via endothelial cell dysfunction and other mechanisms.

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Reflected Pulse Waves In addition to the forward pulse wave, each cardiac cycle generates a reflected wave, originating at areas of arterial impedance mismatch, which travels back up the arterial tree toward the central aorta, altering the arterial pressure waveform. This reflected wave can be noninvasively assessed from recordings of the carotid (25) or radial (35) arterial pulse waveforms by arterial applanation tonometry and high-fidelity micromanometer probes. Dividing the late systolic augmentation of the arterial pulse wave by the distance from the peak to the trough of the arterial waveform (corresponding to the pulse pressure) yields the augmentation index (24). The augmentation index, like the pulse wave velocity, increases with age (Fig. 4B) (24,25). The velocity of the reflected flow wave is proportional to the stiffness of the arterial wall. Thus, in young individuals whose vascular wall is compliant, the reflected wave does not reach the large elastic arteries until diastole. With advancing age and increasing arterial stiffening, the velocity of the reflected wave increases, and the wave reaches the central circulation earlier in the cardiac cycle, during the systolic phase. The pressure pulse augmentation provided by the early return of the reflected wave is an added load against which the aged ventricle must contract. Furthermore, the diastolic augmentation seen in compliant vessels, caused by the late return of the reflected waves, is lost in the elderly, decreasing diastolic blood pressure; this decrease in diastolic pressure has the potential to reduce coronary blood flow because most coronary flow occurs during diastole. Multiple studies (27,36–43) indicate that increased vascular stiffness, over and above blood pressure, is an independent predictor of hypertension, atherosclerosis, CV events, and mortality. In fact, Liao et al. (38) have demonstrated that increased vascular stiffness precedes the development of hypertension. Thus, while a “secondary” increase in large artery stiffness is attributable to an increase in mean arterial pressure that occurs in hypertension, evidence now exists that a “primary” increase in large artery stiffness that accompanies aging gives rise to an elevation of arterial pressure. Normotensive individuals who fall within the upper quartile for measures of arterial stiffness are more likely to subsequently develop hypertension. Observations such as these reinforce the concept that hypertension, at least in part, is a disease of the arterial wall. The mechanisms of ageassociated changes in vascular structure and function and the putative relationship of these changes to development of CV disease are depicted in Table 1. Systolic, Diastolic, and Pulse Pressure Arterial pressure is determined by the interplay of peripheral vascular resistance and arterial stiffness; the former raises both systolic and diastolic pressure to a similar degree, whereas the latter raises systolic but lowers diastolic pressure. A rise in average systolic blood pressure across adult age has been well documented (Fig. 5) (43,44). In contrast, average diastolic pressure (Fig. 5) was found to rise until about 50 years of age, level off from age 50 to 60, and decline thereafter (43,44). Thus, pulse pressure (systolic minus diastolic), a useful hemodynamic indicator of conduit artery vascular stiffness, increases with age. These age-dependent changes in systolic, diastolic, and pulse pressures are consistent with the notion that in younger people blood pressure is determined largely by peripheral vascular resistance, whereas in older individuals it is determined to a greater extent by central conduit vessel stiffness. Because of the decline in diastolic pressure in older men and women in whom systolic pressure is increased, isolated systolic hypertension emerges as the most common

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Table 1 Relationship of Cardiovascular Human Aging in Health to Cardiovascular Disease Age-associated changes

Plausible mechanisms

Cardiovascular structural remodeling * Vascular intimal * Migration of and * matrix thickness production by VSMC Possible derivation of intimal cells from other sources * Vascular stiffness Elastin fragmentation * Elastase activity * Collagen production by VSMC and * cross-linking of collagen Altered growth factor regulation/ tissue repair mechanisms * LV wall thickness * LV myocyte size

* Left atrial size

+ Myocyte number (necrotic and apoptotic death) Altered growth factor regulation Focal collagen deposition * Left atrial pressure/volume

Cardiovascular functional changes Altered regulation of + NO production/effects vascular tone + bAR responses + Cardiovascular * Vascular load reserve + Intrinsic myocardial contractility + b-Adrenergic modulation of heart rate, myocardial contractility, and vascular tone Reduced physical Learned lifestyle activity

Possible relation to human disease Early stages of atherosclerosis

Systolic hypertension Stroke Atherosclerosis Retarded early diastolic cardiac filling * Cardiac filling pressure Lower threshold for dyspnea * Prevalence of lone atrial fibrillation Vascular stiffening; hypertension

Lower threshold for, and increased severity of, heart failure

Exaggerated age Ds in some aspects of cardiovascular structure and function; negative impact on atherosclerotic vascular disease, hypertension, and heart failure

Abbreviations: VSMC, vascular smooth muscle cell; LV, left ventricular; NO, nitric oxide; bAR, b-adrenergic receptor.

form of hypertension in individuals over the age of 50 (43). Isolated systolic hypertension, even when mild in severity, is associated with an appreciable increase in CV disease risk (45,46). On the basis of long-term follow-up of middle-aged and older subjects, however, Framingham researchers have found pulse pressure to be a better predictor of coronary disease risk than systolic or diastolic blood pressures (47). A subsequent Framingham investigation found that pulse pressure was especially informative of coronary risk in older subjects (48) because of the “J”- or “U”-shaped association between diastolic pressure and coronary risk. Thus, consideration of the systolic and diastolic pressures jointly, as reflected in pulse pressure, is preferable to consideration of either value alone.

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Figure 5 Change in blood pressure with age in healthy men (triangles) and women (circles) from the Baltimore Longitudinal Study of Aging. Source: From Ref. 44.

INTERVENTIONS TO RETARD OR PREVENT ACCELERATED ARTERIAL AGING Although the deleterious effects of aging on arterial structure and function may appear inevitable from the discussion above, increasing evidence is accruing that lifestyle modifications, including aerobic exercise and dietary modifications, including reduction in sodium intake, caloric restriction, or weight loss, can prevent or retard the progression of IM thickening (49–51) or arterial stiffening (52,53) and improve endothelial function ((54–57). Perhaps, the most promising of these modifications is caloric restriction, which prolongs maximal lifespan in laboratory animals when begun in youth or middle age. Limited studies in individuals have demonstrated decreases in CV risk factors and inflammatory markers with caloric restriction (51,58). In a recent study, 25 individuals aged 5312 years who had practiced voluntary caloric restriction of *30% for an average of 6.5 years showed markedly lower blood pressure and inflammatory markers compared with controls matched for age and gender (58). In addition, the calorie restricted group demonstrated higher transmitral early diastolic flow measures, similar to those of younger adults (58). Whether such beneficial effects can be derived by initiating caloric restriction at older ages is unclear. Pharmacological interventions can also favorably modulate the elements of arterial aging. In animal models, chronic angiotensin converting enzyme inhibition or angiotensin receptor blockade, begun at an early age, markedly delays the progression of ageassociated arterial remodeling, e.g., the IM thickening and rupture of internal elastic lamina (59,60), attenuates mitochondrial dysfunction, reduces reactive oxygen species,

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enhances NO bioavailability, reduces fibrosis, retards vascular and cardiac aging, and prolongs life (61–67). It is thus far unproven if such treatment can prevent or retard unsuccessful aging of the vasculature in animals or humans of younger to middle age who exhibit excessive subclinical evidence of accelerated arterial aging. Recent studies have shown that breaking nonenzymatic collagen cross-links with a novel thiazolium agent reduces arterial stiffness, both in nonhuman primates (68) and in humans (69). CARDIAC STRUCTURE AND RESTING FUNCTION Before the advent of echocardiography, autopsy was essentially the only method for obtaining reliable measurements of cardiac structure in normal persons. Such studies were obviously flawed by their inherent selection bias. A large autopsy series by Linsbach et al. (70) in 7112 patients demonstrated an increase in cardiac mass of 1 to 1.5 g/yr between the ages of 30 and 90 years. Because the study included individuals with CV disease, the age-associated increase in heart weight may derive, at least in part, from the development of cardiac pathology. An autopsy study of 765 normal hearts from persons 20 to 99 years old who were free from both hypertension and CAD showed that heart weight indexed to body surface area was not age related in men but increased with age in women, primarily between the fourth and seventh decades (71). In hospitalized patients without evidence of CV disease, Olivetti et al. (72) observed an age-associated reduction of left ventricular (LV) mass mediated by a decrease in estimated myocyte number, although myocyte enlargement occurred with age. These investigators subsequently found a higher prevalence of apoptotic myocytes in older male than in female hearts, which paralleled a decline of LV mass with age in men but not in women (73). Beginning in the 1970s, the widespread application of echocardiography finally allowed accurate noninvasive assessment of age changes in cardiac structure and function. In healthy normotensive BLSA men, Gerstenblith et al. (74) observed a 25% increase in echocardiographic LV posterior wall thickness between the third and eighth decades, a finding replicated by others (75,76). Because LV diastolic cavity size was not significantly age related in the BLSA (64), calculated LV mass also increased substantially with age. Thus, an apparent discrepancy existed between the unchanged or decreased LV mass with age seen at autopsy and the increase in LV wall thickness and calculated LV mass observed by echocardiography. A recent study in BLSA volunteers using cardiac magnetic resonance imaging (MRI) to estimate LV mass helps to resolve these divergent findings (77). Unlike standard echocardiography, which provides one- and two-dimensional measurements, MRI assesses LV size in three dimensions. In 136 men and 200 women without CV disease, MRI-derived LV wall thickness increased with age (Fig. 6, upper panels), and short-axis diastolic dimension was not age related, similar to earlier echocardiographic findings. In contrast, LV length declined with age in both sexes (i.e., the LV became more spherical) (Fig. 6, middle panels) (77). Thus, MRI-derived LV mass was unrelated to age in women and demonstrated an age-associated decline in men (because of their lesser age-related increase in wall thickness), similar to recent autopsy findings (Fig. 6, lower panels) (73). Three-dimensional echocardiography has confirmed this preservation of LV mass across age in women and a reduction of LV mass in older men (78). With advancing age, therefore, the normal LV becomes thicker and more spherical. Although the mechanisms for the age-associated remodeling of the LV and increase in myocyte size are not clear, it is attractive to suggest that they are adaptive to the arterial

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changes that accompany aging. Putative stimuli for cardiac cell enlargement with age are an increase in vascular load due to arterial stiffening and a stretching of cells due to dropout of neighboring apoptotic myocytes (79,80). Phenotypically, the age-associated increase in LV thickness resembles the LV hypertrophy that develops from hypertension. This finding, coupled with the increase in systolic blood pressure that occurs over time even in healthy individuals, has led to consideration of aging as a muted form of hypertension. In older rodent hearts, which demonstrate a similar increase in LV mass and myocyte size as observed in humans, a stretching of cardiac myocytes and fibroblasts releases growth factors such as angiotension II, a known stimulus for apoptosis (81). In addition, enhanced secretion of atrial natriuretic (82) and opioid (83) peptides is observed. Echocardiographic aortic root diameter dilates modestly with age, approximating 6% in BLSA men between the fourth and eighth decades (74). Similarly, the aortic knob diameter increased from 3.4 to 3.8 cm on serial chest x-rays over 17 years (84). Such aortic root dilation provides an additional stimulus for LV hypertrophy because the larger volume of blood in the proximal aorta represents a greater inertial load that must be overcome before LV ejection can begin. As previously noted, the resting supine LV short-axis diastolic dimension is not significantly related to age; the resting LV systolic dimension is, similarly, unrelated to age. Thus, echocardiographic LV shortening fraction (64) and radionuclide LV ejection fraction (85,86), the two most common measures of global LV systolic performance, are unaffected by age in healthy normotensive persons. Because LV stroke volume (SV) is the difference of LV end-diastolic (EDV) and end-systolic volumes (ESV), the supine LV stroke volume is also unrelated to age (74). Prolonged contractile activation of the thickened LV wall (87) maintains a normal ejection time in the presence of the late systolic augmentation of aortic impedance, preserving systolic cardiac pump function at rest. However, a “downside” of prolonged contractile activation is that at the time of the mitral valve opening, myocardial relaxation is less complete in older than in younger individuals, contributing to a reduced early LV filling rate. In contrast, therefore, to the preservation of resting LV systolic performance across the adult age span, LV diastolic performance is profoundly altered by aging. Reduced mitral valve E–F closure slope on M-mode echocardiography first documented these age changes in diastolic performance (74,75). Pulsed Doppler (88,89) and radionuclide (90) techniques confirmed that the transmitral early diastolic peak-filling rate declined by *50% between ages 20 and 80 years (Fig. 7). Conversely, peak A-wave velocity, which represents late LV filling facilitated by atrial contraction, increases with age. This greater atrial contribution to LV filling is accomplished via a modest age-associated increase in left atrial size demonstrable on echocardiography. Tissue Doppler and color M-mode techniques, both less influenced by preload and afterload than pulsed Doppler, have confirmed the age-associated reduction in early diastolic filling rate and increased late filling (91,92). Because the resting LV end-diastolic volume is preserved across adult age

Figure 6 Effect of age on LV geometry and mass, derived from three-dimensional cardiac magnetic resonance imaging in normotensive BLSA volunteers. (A) LV wall thickness increases with age in both sexes, though more steeply in women. (B) The LV long axis dimension declines with age in both sexes, but more steeply in men, whereas minor axis dimension (not shown) is unrelated to age. (C) Calculated LV mass is not age-related in women but declines with age in men. Abbreviations: LV, left ventricular; BLSA, Baltimore Longitudinal Study of Aging. Source: Adapted from Ref. 77.

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Figure 7 Changes with age in peak early diastolic filling rates derived from radionuclide ventriculography at rest and during maximal upright cycle ergometry. The inset shows the transmitral flow velocity profile derived from Doppler echocardiography in a young and older adult. Note the shift from a dominant early (E) filling wave in the young to a dominant late (A) filling wave in the elderly. Source: Adapted from Ref. 90.

in BLSA volunteers, the augmented atrial contribution to LV filling in older adults can be considered a successful adaptation to the reduced early diastolic filling rate in the thicker, and presumbably stiffer, senescent LV. Thus, the relative importance of early and late diastolic LV filling is reversed with advanced age. Impairment of early LV filling with age may derive in part from reduced LV diastolic compliance due to the increase in LV wall thickness with age. Although an age-associated reduction in ventricular compliance remains unproven in humans, animal studies in both intact hearts and isolated cardiac muscle have detected prolonged isovolumic relaxation and increased myocardial diastolic stiffness. The slower isovolumic relaxation observed in cardiac muscle from older animals (93) may be secondary to diminished rate of Ca2þ accumulation by the sarcoplasmic reticulum (94). A conceptual framework for the cardiac adaptations to age-associated arterial stiffening is shown in Figure 8. Whereas the diminished early diastolic filling rate with age may not compromise resting end-diastolic volume or stroke volume, an underlying reduction of LV compliance might cause a greater rise in LV diastolic pressure in older persons, especially during stress-induced tachycardia, thus causing a lower threshold for dyspnea than in the young. It might also be anticipated that the loss of atrial contribution to LV filling that occurs during atrial fibrillation would elicit a greater deterioration of diastolic performance in older than in younger individuals. Indeed, it is attractive to speculate that the frequent occurrence of heart failure in the elderly despite preserved LV systolic function derives, at least in part, from the age-associated impairment of early diastolic filling (Table 1). CV Physical Findings in Older Adults Several age-associated alterations in CV structure and function may manifest themselves during the CV examination. Because of the stiffening of the large arteries, systolic blood

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Figure 8 Conceptual framework for the cardiovascular adaptations to arterial stiffening that occur with aging. Abbreviation: LV, left ventricular.

pressure is often elevated with a normal or low diastolic blood pressure. Therefore, the carotid artery upstroke is usually brisk in the elderly and may mask significant aortic valve stenosis. The apical cardiac impulse may be difficult to palpate secondary to senile emphysema and chest wall deformities. Respiratory splitting of the second heart sound is audible in only *30–40% of individuals older than 60 years, presumably because of reduced compliance of the pulmonary vasculature. In contrast, an S4 gallop is commonly heard in older but not younger persons because of the age-associated increase in late diastolic filling mediated by vigorous atrial contraction into a thicker-walled, less compliant LV. A soft basal ejection murmur occurs in 30–60% of the elderly. This murmur is thought to arise from a dilated, tortuous aorta or from sclerosis of the aortic valve. CV RESPONSE TO STRESS The CV response to stress (e.g., to increases in arterial pressure, to postural maneuvers, or to physical exercise) in older individuals is of considerable interest in clinical medicine. First, physicians are often called upon to provide advice and information concerning the CV potential of the elderly (e.g., the effect or importance of conditioning status on the maintenance of function). Second, the CV response to stress is important in assessing the ability of older individuals to respond to disease states. Third, the CV response to stress has considerable value in the diagnosis and management of patients with CV disease. Despite the high prevalence of CV disease among older Americans, it is of substantial importance to understand the exercise capabilities of disease-free CV elders. Exercise testing is a diagnostic tool that is frequently utilized to detect and quantify the severity of CV disease. It is very clear that the value of such diagnostic tests and the validity of their interpretation depend on precise information regarding the normal limits of such stresstesting procedures relative to age.

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Orthostatic Stress Perturbations from the supine, basal state activate CV reflex mechanisms and mediate the utilization of CV reserve function. The result of these reflex mechanisms is enhanced blood flow to, and preservation of arterial pressure within, selected body organs. In response to a change from supine to upright posture, an increase in systemic vascular resistance maintains the mean arterial pressure. A change in blood flow from the heart depends on the product of changes in heart rate and stroke volume index (SVI), the latter being determined by the changes in end-diastolic volume index (EDVI) and end-systolic volume index (ESVI). Changes in EDVI are determined, in part, by changes in venous return, which depends on the ability of the blood to flow through the vascular system, and to changes in ESVI. In healthy, community-dwelling elders, arterial pressure changes little with the assumption of upright posture, and postural hypotension or acute orthostatic intolerance (i.e., dizziness or fainting when assuming an upright from a supine position or during a passive tilt) is uncommon. Orthostatic hypotension (OH), defined by a decline of systolic blood pressure by
20 mmHg or diastolic blood pressure by
10 mmHg, occurred in 16% of volunteers aged 65 years and older from the Cardiovascular Health Study (95) and in 7% of men aged 71 to 93 years from the Honolulu Heart Program (96); in both of these older cohorts the prevalence of OH increased with age. In the former study, OH was associated with higher supine blood pressure, greater LV wall thickness, and smaller LV cavity size (97). In the latter study, OH was an independent predictor for mortality (relative risk [RR] ¼ 1.64), and there was a linear relationship between the magnitude of orthostatic decline in systolic blood pressure and 4-year mortality rate (96). In contrast to healthy, community-dwelling older volunteers, OH and orthostatic intolerance are common in debilitated institutionalized elders with chronic illnesses. Within such populations, the likelihood for OH is increased among individuals who exhibit very low LV filling rates and small EDVI and SVI in the supine position (98). In such individuals, however, the effects of advanced age cannot be dissociated from those of profound deconditioning and multiple diseases and medications. With advancing age, the acute heart rate increase to orthostatic stress decreases in magnitude and takes longer to achieve. The baroreceptor sensitivity (i.e., the slope of the relationship of the change in heart rate versus the change in arterial pressure) is negatively correlated with age and resting arterial pressure (99). The low-pressure baroreceptor, or cardiopulmonary reflex, also decreases with age in normotensives, but not in hypertensives. Despite the lesser heart rate increase during orthostatic stress in older than in younger BLSA volunteers, the SVI reduction tends to be less in the older group; thus, the postural change in cardiac output does not vary significantly with age, because a lesser reduction in SVI balances the lesser increase in heart rate in older individuals (100). Similarly, studies have found cardiac output to be reduced with age in the supine position because of a reduced SVI in older versus younger men; this age effect was abolished in the sitting position because of lesser reduction in SVI in the older men on sitting. Responses to gradual tilt or to graded lower body negative pressure in older individuals are similar to responses to change in body position: SVI and cardiac output decrease less in older adults, offsetting their blunted heart rate increase (101). A lesser reduction in SVI in older versus younger individuals following a postural stress implies either a smaller reduction in EDVI or a greater reduction in ESVI in older individuals. Reduced venous compliance in older versus younger individuals, advanced as a mechanism to account for a lesser peripheral fluid shift during orthostatic maneuvers, could preserve cardiac filling

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volume and maintain SV in the upright position in healthy elderly individuals (102). A reduction in the venodilatory response to b-adrenergic stimulation with preservation of the a-adrenergic vasoconstrictor response may contribute to a reduced venous compliance with aging. Pressor Stress Acute increases in blood pressure represent another common CV stress. Sustained, isometric handgrip increases both arterial pressure and heart rate. The response varies in magnitude in proportion to the relative level and duration of effort. After sustained submaximal or maximal handgrip, heart rate was observed to increase more in younger than in older healthy individuals, whereas blood pressure increased more in older persons (103,104). In BLSA volunteers, 3 minutes of submaximal sustained handgrip elicited mild increases in echocardiographic LV diastolic and systolic dimensions and atrial filling fraction; these increases correlated positively with age (104). Thus, pressor stress accentuated the age-associated dependence on late diastolic filling. Application of a pressor stress has also been used to assess the intrinsic myocardial reserve capacity. In healthy BLSA individuals, a 30 mmHg increase in systolic blood pressure induced by phenylephrine infusion in the presence of b-adrenergic blockade induced significant echocardiographic LV dilatation at end diastole in healthy older (60–68 years), but not in younger (18–34 years), men: the cardiac dilatation occurred in older men despite a smaller reduction in heart rate (105), analagous to the handgrip response. Thus, an apparent age-associated decrease in intrinsic myocardial contractile reserve occurs in response to an acute increase in afterload; the senescent heart dilates to preserve SVI via the Frank-Starling mechanism. Aerobic Exercise Capacity and Aging The ability to perform oxygen-utilizing (i.e., aerobic) activities is a fundamental requirement of independent living and is probably the best-studied CV stressor. The accepted standard for aerobic fitness is maximum oxygen consumption rate (VO2max), the product of cardiac output (the central component) and arteriovenous oxygen difference (the peripheral component). In healthy adults, VO2max is up to 15 times greater than VO2 at rest. This is accomplished by a four- to fivefold increase in cardiac output and up to a threefold widening of the arteriovenous oxygen difference; the latter is due to both a dramatic increase in the relative proportion of cardiac output delivered to working muscles and an increased oxygen extraction by these muscles. Because the total body VO2max is strongly influenced by muscle mass, VO2max is typically compared across individuals by normalizing for body weight. Numerous studies have documented that treadmill VO2max, adjusted for body weight, declines with age. In cross-sectional studies, the decline typically approximates 50% across the adult age span. However, the extent of the VO2max decline with aging varies among studies, depending on age ranges, differences in body weight and composition, and differences in habitual physical activity among the individuals studied. Longitudinal studies generally report a more pronounced age-associated decline in VO2max than do cross-sectional studies. In BLSA volunteers rigorously prescreened to exclude CV or lung disease, VO2max declines by *50% between the third and ninth decades by cross-sectional analysis (Fig. 9) (106,107). Cross-sectional studies, such as those in Figure 9, are usually interpreted to indicate that VO2max declines linearly with age. A recent analysis in this same population, however, demonstrated that the longitudinal decline in aerobic capacity is not constant

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Figure 9 Cross-sectional declines in peak VO2 per kg body weight in healthy BLSA men and women. Abbreviation: BLSA, Baltimore Longitudinal Study of Aging. Source: From Ref. 107.

across adulthood as assumed by cross-sectional studies, but accelerates markedly with successive age decades, especially in men, regardless of physical activity levels (Fig. 10) (108). When the components of VO2max were examined, the longitudinal decline in oxygen pulse (VO2 per heart beat) mirrored that of VO2max, whereas maximal heart rate decreased only 4–6% per decade regardless of starting age (Fig. 10). Although ageassociated loss of muscle mass and increase in body fat also contribute to the reduction in VO2max with aging, the pattern of accelerated VO2max decline with age persists even after normalizing it for fat-free mass rather than body weight (108). Despite the similar rates of decline in VO2max with age regardless of physical activity level, it should be emphasized that at any age the more active quartiles maintain a higher VO2 max than their sedentary peers. The accelerated decline of aerobic capacity has important implications regarding functional independence and quality of life. One should bear in mind that the data in healthy BLSA volunteers represent a “best case scenario.” The superimposition of CV or

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Figure 10 Longitudinal change in peak VO2 and its components (maximal heart rate and O2 pulse) in healthy BLSA volunteers. In both sexes, the decline in maximal heart rate is only *5% per decade and is relatively constant across age. However, the decline in O2 pulse, encompassing both stroke volume and peripheral oxygen delivery and utilization, declines more rapidly in older adults, paralleling the decline in peak VO2. Abbreviation: BLSA, Baltimore Longitudinal Study of Aging. Source: Adapted from Ref. 108.

pulmonary disease as well as the deconditioning commonly seen in the elderly because of their sedentary lifestyle accentuates this decline in VO2max. Because activities of daily living typically require a fixed aerobic expenditure, they require a significantly larger percent of VO2max in an older than a younger person. Once the energy required of an activity approaches or exceeds the aerobic capacity of an elderly individual, he or she will likely be unable to perform it. Thus, it is not surprising that a low aerobic capacity comprises one of the five components of the “frailty phenotype” (109). Another potential contributor to exercise intolerance with aging is a greater metabolic debt incurred during exercise that persists during recovery. For several minutes after a bout of aerobic exercise, the body continues to consume oxygen at a higher rate than at rest. This “oxygen debt” incurred during recovery can comprise 14–20% of the total aerobic expenditure. In a recent study, the VO2 consumed by healthy older persons during recovery from exercise exceeded that in the young by more than 30% (110). Although the precise causes of this greater VO2 use during recovery in the elderly is unclear, increased circulating catecholamine levels (111) and a higher core temperature that occur during exercise and early recovery in deconditioned older adults (112) may be contributory. Because of the difficulty in imaging the heart during treadmill exercise, cycle ergometry has been used to dissect the relative contributions of cardiac factors in the ageassociated decline in aerobic capacity (Table 2). During upright cycle ergometry, the peak VO2 of healthy BLSA participants averages about 80% of that during treadmill exercise, regardless of age. The primary factor limiting the duration and intensity of cycle exercise is usually leg fatigue. Peak cycle work rate and VO2 decline by *50% between ages 20 and 90 years in healthy, nonathletic BLSA men and women, attributable to declines of *30% in cardiac output and 20% in arteriovenous oxygen difference (Table 2) (113). The age-associated decrease in cardiac index at maximal effort during upright cycle exercise (Fig. 11F) is due entirely to a reduction in heart rate (Fig. 11E), as the LVSVI does not decline with age in either gender (Fig. 11D) (114). However, the manner in which SVI is achieved during maximal exercise varies dramatically with aging. Although older individuals have a blunted capacity to reduce ESVI (Fig. 11B) and to increase ejection fraction (Fig. 11C), this deficit is offset by a larger EDVI (Fig. 11A) (114). Thus, a “stiff heart” that prohibits sufficient filling between beats during exercise does not

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Table 2 Changes in Maximal Aerobic Capacity and Its Determinants Between Ages 20 and 80 Years in Healthy Volunteers Oxygen consumption (A-V)O2 difference Cardiac output Heart rate Stroke volume Preload EDV Afterload Vascular (SVR) Cardiac (ESV) Cardiac (EDV) Contractility Ejection fraction Plasma catecholamines Cardiac and vascular Responses to b-adrenergic stimulation

+ (50%) + (20%) + (30%) + (25%) no D * (30%) * * (30%) * (275%) * (30%) + (60%) + (15%) * +

Abbreviations: A-V, arteriovenous; EDV, end-diastolic volume; ESV, endsystolic volume; SVR, systemic vascular resistance.

characterize aging in healthy individuals. The larger EDVI in healthy older versus younger individuals during vigorous aerobic exercise is due in part to a longer diastolic interval (i.e., slower heart rate) and to a greater amount of blood remaining in the heart at end systole (Fig. 11B) (114). Given the accelerated decline in VO2max with age, an important question is whether aerobic training of sedentary older adults can improve their CV reserve capacity. It has been amply documented that physical conditioning of older persons can substantially increase their maximum aerobic work capacity. In a recent meta-analysis of 41 trials in 2102 individuals aged 60 and older, aerobic training elicited a 16.3% mean increase in VO2max (115). The extent to which this conditioning effect results from enhanced central cardiac performance versus augmented peripheral mechanisms, including changes in skeletal muscle mass, varies with the characteristics of the population studied, the type and degree of conditioning achieved, gender, body position during study, and likely genetic factors. A longitudinal study of older men during upright cycle ergometry indicates that aerobic training enhances VO2max in part by increases in the maximum cardiac output due to augmented maximum SV and in part by increasing the arteriovenous oxygen difference (116). The augmentation of maximum SV is due primarily to an augmented reduction of LVESV and, thus, a concomitant increase in LV ejection fraction; however, conditioning status had minimal effect on LVEDV during exercise in older adults. This contrasts with the effect of physical conditioning in younger persons, which substantially increases EDV and SV on the basis of the Frank-Starling mechanism, as well as via an enhanced LV ejection fraction. In contrast to the improved LV ejection post-training, the maximal heart rate of older (as well as younger) persons does not vary with conditioning status. Thus, physical conditioning of older persons does not appear to offset the age-associated deficiency in sympathetic modulation. Rather, increased LV ejection from aerobic training in this age group appears to derive from the reduction in vascular afterload, as reflected in a reduced pulse wave velocity (117) and carotid augmentation index, with possible contribution from augmented maximum intrinsic myocardial contractility. Furthermore, aerobic training in

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Figure 11 Scatter plots of left ventricular volumes (A, B), ejection fraction (C), stroke volume (D), heart rate (E), and cardiac index (F) during maximal graded upright cycle exercise in healthy BLSA volunteers, carefully screened to exclude silent coronary artery disease. Note the similar age changes in men and women and the increasing heterogeneity with age in the end-systolic volume index, ejection fraction, and heart rate. Abbreviation: BLSA, Baltimore Longitudinal Study of Aging. Source: Adapted from Ref. 114.

sedentary older adults reduced their oxygen debt immediately post-exercise by nearly 30%, translating into an 18% increase in exercise efficiency; in contrast, efficiency did not change in younger persons after training (110). MECHANISMS OF IMPAIRED LV EJECTION DURING MAXIMAL AEROBIC EXERCISE IN HEALTHY OLDER ADULTS The ejection fraction at maximal exercise and its increase from rest are sometimes used clinically as a diagnostic tool to detect and quantify the severity of cardiac disease, particularly CAD. Exercise ejection fraction is thus of considerable clinical interest. The impaired ability of healthy older men and women to reduce LV ESVI during vigorous

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exercise accounts for their smaller increase in ejection fraction from rest and their lower maximal value compared to younger individuals (Fig. 11C) (114). A blunted LV ejection fraction response during exercise is even more prominent in older individuals with exercise-induced silent myocardial ischemia than in those without evident ischemia, due to a more pronounced inability to reduce ESVI (118). The underlying mechanisms for the age-associated reduction in maximum ejection fraction are multifactorial and include (1) a reduction in intrinsic myocardial contractility, (2) an increase in vascular afterload, (3) arterial-ventricular load mismatching, and (4) a diminished effectiveness of the autonomic modulation of both LV contractility and arterial afterload. Although these age-associated changes in CV reserve per se are insufficient to produce clinical heart failure, they appear to lower the threshold for developing symptoms and signs of heart failure and adversely influence its clinical severity and prognosis for any level of disease burden (Table 1). Myocardial Contractility How aging affects factors that regulate intrinsic myocardial contractility in humans is incompletely understood because the effectiveness of intrinsic myocardial contractility in the intact circulation is difficult to separate from loading and autonomic modulatory influences on contractility. Given that the heart rate per se is a determinant of the myocardial contractile state, a deficit in maximal intrinsic contractility of older persons might be expected on the basis of their reduced maximum heart rate. Supporting evidence for reduced LV contractility with aging during stress comes from a study in which the LV of older but not younger healthy BLSA men dilated at end diastole in response to a given increase in afterload during b-adrenergic blockade (105). Myocardial systolic stiffness or elastance, one index of LV contractile performance, is best approximated by the slope of the end-systolic pressure (ESP) on ESV coordinates measured across a range of EDVs at rest; this slope has not been determined in a healthy population across a broad age range and by convention cannot be accessed during exercise. A single point depicting ESP/ESV as a contractility index at each overall CV level of performance presents an age-associated pattern of myocardial contractile reserve that is nearly identical to the age-associated change in the pattern of ejection fraction in Figure 11C (114). LV Afterload Cardiac afterload has two components, one generated by the heart itself and the other by the vasculature. The cardiac component of afterload during exercise can be expected to increase slightly with age because the heart size increases in older persons throughout the cardiac cycle during exercise (114). The vascular load on the heart has four components: conduit artery compliance characteristics, reflected pulse waves, resistance, and inertance. Inertance is determined by the mass of blood in the large arteries that requires acceleration prior to LV ejection. As the central arterial diastolic diameter increases with aging (26,74), the inertance component of afterload likely increases. Thus, each of the pulsatile components of vascular load, measured at rest, increases with age. Augmented LV afterload in older versus younger persons during exercise likely plays a major role in the failure of the acute LVESV reserve with advancing age. However, the extent to which the age-associated increases in afterload at rest becomes more pronounced during exercise is not known with certainty. Whereas the exaggerated cardiac dilation from the resting level that occurs during vigorous exercise in healthy older individuals suggests an exercise-induced increase in cardiac afterload, it has not

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been possible to noninvasively assess PWV, augmentation index, aortic diameter, or impedance during exercise. Although some indices of afterload, such as arterial pressure and systemic vascular resistance, have been determined during exercise, their levels are confounded by the decrease in maximum exercise capacity that occurs with age. Arterial/Ventricular Load Matching Optimal ejection of blood from the heart occurs when ventricular and vascular loads are matched. The precise cardiac and vascular load matching that is characteristic of younger persons is thought to be preserved at older ages, at least at rest, because the increased vascular stiffness in older persons at rest is matched by increased resting ventricular stiffness (119). For the ejection fraction to increase during exercise, the LV end-systolic elastance (ELV), i.e., the ESP/ESV ratio, must increase to a greater extent than the effective vascular elastance (EA), i.e., ESP/stroke volume. With increasing age, however, ELV fails to increase in proportion to the increase in EA; hence, the EA/ELV during exercise in older persons decreases to a lesser extent than it does in younger persons (120). This altered arterialventricular load matching in older versus younger persons during exercise is a mechanism for the deficit in the acute LV ejection fraction reserve that typically accompanies advancing age. Thus, the LV ejection fraction, often considered a measure of LV pump function, is determined by both cardiac and vascular properties, each of which changes with age. Acute pharmacological reduction in both cardiac and vascular components of LV afterload by sodium nitroprusside infusions in older, healthy BLSA volunteers augments LV ejection fraction in these subjects at rest and throughout upright cycle exercise (121). Because of concomitant reductions in preload and afterload during sodium nitroprusside infusion, the LV of older persons delivers the same stroke volume and cardiac output as prior to infusion while working at a smaller size. In another study, acute infusion of the calcium channel blocker verapamil, which reduced exercise afterload but not preload, improved LV ejection and oxygen utilization during submaximal exercise in healthy older volunteers (119). Sympathetic Modulation During acute exercise and other stresses, sympathetic modulation of the CV system increases heart rate, augments myocardial contractility and relaxation, reduces LV afterload, and redistributes blood to working muscles and skin to dissipate heat. All of the factors that have been identified to play a role in the deficient CV regulation with aging, i.e., heart rate, afterload (both cardiac and vascular), myocardial contractility, and redistribution of blood flow, exhibit a deficient sympathetic modulatory component. Sympathetic Neurotransmitters Apparent deficits in sympathetic modulation of cardiac and arterial functions with aging occur in the presence of elevated neurotransmitter levels. Plasma levels of norepinephrine and epinephrine, during any perturbation from the supine basal state, increase to a greater extent in older than in younger healthy humans (83,111). This increase appears to be a compensatory response to the reduced cardiac b-receptor density with advancing age (122). The age-associated increase in plasma levels of norepinephrine results from an increased cardiac spillover into the circulation and, to a lesser extent, to reduced plasma clearance. Deficient norepinephrine reuptake at nerve endings has been suggested as the primary mechanism for increased spillover. During prolonged submaximal exercise, however, diminished neurotransmitter reuptake might also be associated with reduced

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release and spillover in older adults (123), contributing to the age-associated deficit in cardioacceleration and LV systolic performance seen during such an exercise (124). Deficits in Cardiac b-Adrenergic Receptor Signaling The age-associated increase in neurotransmitter spillover into the circulation during acute stress implies a greater heart and vascular receptor occupancy by these substances. Experimental data indicate that this condition leads to desensitization of the postsynaptic signaling components of sympathetic modulation. The deficits in b-adrenergic signaling with aging are attributable in part to reduction in b-receptor numbers, deficient G-protein coupling of receptors to adenyl cyclase and, possibly, to age-associated reductions in the amount or activation of adenyl cyclase, leading to a relative reduction in the ability to augment cellular cAMP in response to b-receptor stimulation in the older heart. Numerous studies support the concept that the efficiency of postsynaptic b-adrenergic signaling declines with aging (122). One line of evidence derives from the observation that acute b-adrenergic receptor blockade changes the exercise hemodynamic profile of younger persons to resemble that of older ones. Thus, the reduction in heart rate during exhaustive aerobic exercise in the presence of acute b-adrenergic blockade is greater in younger than in older subjects, and significant b-adrenergic blockade–induced LV dilatation occurs only in younger group (125). In addition, the age-associated deficits in early LV diastolic filling rate, both at rest and during exercise, are abolished by acute b-adrenergic blockade (90). However, acute b-adrenergic blockade causes SVI to increase to a greater extent in younger than in older individuals, due in part to the greater increase in LV filling time in the young, caused by greater reduction in their maximal heart rate (125). When perspectives from intact humans to subcellular biochemistry in animal models are integrated, a diminished responsiveness to b-adrenergic modulation is among the most consistently observed CV changes that occur with advancing age. Age-associated alterations in CV function that exceed the identified limits for healthy elderly individuals most likely represent interactions of aging per se with severe physical deconditioning and/ or CV disease, both of which are highly prevalent among older adults. RELEVANT AGING CHANGES IN OTHER ORGAN SYSTEMS Because of the close relationships between the CV system and other organs, it is important to recognize some of the more salient non-CV changes that occur with age. In the lungs, loss of elastic recoil causes reduced emptying and thus reduced vital capacity and minute ventilation during vigorous exercise. Plasma and total blood volumes decline moderately with age. Age-related loss of skeletal muscle mass, termed sarcopenia, is paralleled by reduced muscle strength, a major cause of disability and reduced quality of life in the elderly. A similar loss of bone occurs with age and is exacerbated by estrogen deficiency in postmenopausal women, leading to a marked increase in fracture risk. Additionally, age-associated nephrosclerosis results in loss of renal parenchyma and reductions in renal plasma flow, creatinine clearance, plasma rennin activity, and plasma aldosterone. These renal changes decrease the elimination of renally excreted drugs, attenuate responses to sodium restriction and volume expansion, and increase the risk for hyperkalemia. Although creatinine clearance typically declines by *50% between the third and ninth decades, serum creatinine changes minimally because of the parallel loss of muscle mass.

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ELECTROCARDIOGRAPHY AND ARRHYTHMIAS Conduction System The cardiac conduction system undergoes multiple changes with age that affect its electrical properties and, when exaggerated, cause clinical disease. A generalized increase in elastic and collagenous tissue commonly occurs. Fat accumulates around the sinoatrial node, sometimes creating partial or complete separation of the node from the atrial tissue. In extreme cases, this may contribute to the development of sick sinus syndrome. A pronounced decline in the number of pacemaker cells generally occurs after age 60; by age 75, less than 10% of the number seen in young adults remain. A variable degree of calcification of the left side of the cardiac skeleton, which includes the aortic and mitral annuli, the central fibrous body, and the summit of the interventricular system, is observed. Because of their proximity to these structures, the atrioventricular (A-V) node, A-V bifurcation, and proximal left and right bundle branches may be damaged or destroyed by this process, resulting in A-V or intraventricular block. ELECTROCARDIOGRAPHY Alterations in cardiac anatomy and electrophysiology with age often manifest themselves on the ECG. Because the resting EGG remains the most widely used cardiac diagnostic test, a review of these aging changes is relevant to distinguish them from those imposed by disease. Sinus Node Function Whereas supine resting heart rate is unrelated to age in most studies (Table 3; Fig. 12, upper panel), the phasic variation in R–R interval known as respiratory sinus arrhythmia declines with age (126,127). Similarly, a reduced prevalence of sinus bradycardia on resting ECG is evident by the fourth decade (126). Because both sinus arrhythmia and sinus bradycardia are indices of cardiac parasympathetic activity, the age-associated reduction in parasympathetic function (127) may mediate both findings. Spectral analysis of heart rate variability has confirmed an age-related reduction of highfrequency (0.15–0.45 Hz) oscillations indicative of vagal efferent activity (Fig. 12, lower panel) (128,129). Although physical conditioning status influences autonomic tone, a cross-sectional study in BLSA volunteers demonstrated that the deconditioning that usually accompanies the aging process plays only a minor role in the age-associated

Table 3 Normal Age-Associated Changes in Resting ECG Measurements Measurement R–R interval P-wave duration P–R interval QRS duration QRS axis QRS voltage Q–T interval T-wave voltage

Change with age No change Minor increase Increase No change Leftward shift Decrease Minor increase Decrease

Effect on mortality None None None None Probable increase None

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Figure 12 Mean RR interval (RRI) and respiratory sinus arrhythmia (RSA) during 3 min of sitting in healthy BLSA men (closed circles and dashed line) and women (open circles and solid line). Whereas RRI (top) was unrelated to age in either sex, RSA (bottom) declined similarly with age in women (r ¼ 0.61; p < 0.001) and men (r ¼ 0.59; p < 0.001). Abbreviation: BLSA, Baltimore Longitudinal Study of Aging. Source: From Ref. 129.

blunting of these high-frequency oscillations (129). Patients with organic heart disease demonstrate a reduced respiratory sinus arrhythmia compared to age-matched normal individuals. A blunting of high-frequency oscillations in apparently healthy older volunteers is predictive of future coronary events (130) and total mortality (131). Time domain indices of heart rate variability also decline substantially with age; the pattern of decline varies with the specific time domain measure (132). Younger men generally display higher time domain indices than younger women, but this gender difference narrows or disappears at older ages. In a Swiss population of healthy persons aged 50 years and older, CV risk factors, such as hypertension, smoking, non-high-density lipoprotein cholesterol, and C-reactive protein, were each associated with reduced heart rate variability during 24-hour ECG recordings (133). On the resting ECG, sinus bradycardia below 50 bpm was found in 4.1% of 1172 healthy, nonendurance-trained, unmedicated participants aged 40 years and older from the BLSA; the prevalence was similar in men (3.9%) and women (4.5%) (134). Individuals with unexplained sinus bradycardia (mean age 58 years) had a significantly greater prevalence of associated conduction system abnormalities than nonbradycardic age- and sex-matched controls, but there was no difference in the incidence of future coronary events (angina pectoris, myocardial infarction, or cardiac death) over a 5.4-year mean

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follow-up period (134). Sinus bradycardia due to sick sinus syndrome is seen almost exclusively in the elderly and probably derives in part from the marked decline in the number of pacemaker cells in the sinoatrial node. In the absence of organic heart disease, such bradycardia is not associated with increased cardiac mortality (134,135). P Waves Paralleling the echocardiographic increase in left atrial size, the prevalence of left atrial abnormality, defined by a negative P terminal force in lead V1 of at least 0.04 mm-s, increases with age. Among 588 institutionalized elderly, such a P terminal force was only 32% sensitive, although 94% specific, for echocardiographic left atrial enlargement (136). A small increment in P-wave duration of about 8 milliseconds from the third to seventh decades has been observed (137), presumably secondary to the modest increase in left atrial size. There does not appear to be any increase in ECG evidence of right atrial enlargement with age when individuals with significant chronic obstructive lung disease are excluded. P--R Interval With advancing age, the P–R interval undergoes a modest but significant prolongation (138–140). In a database of 46,129 persons with very low probability of CV disease, mean PR interval increased from 148 to 166 milliseconds in women and from 153 to 182 milliseconds in men between the third and ninth decades (138). An increase in P–R interval from 159 to 175 milliseconds in men and from 156 to 165 milliseconds in women occurred between the ages of 30 and 72 years in BLSA volunteers (139). By highresolution signal-averaged surface ECGs, the prolongation of A-V conduction was localized proximal to the His bundle deflection, but within the P–R segment, presumably reflecting delay within the A-V junction. In seven older men with first-degree A-V block, there was a similarly located but more pronounced A-V junctional delay (112). Using the conventional upper limit of 0.20 seconds, the prevalence of first-degree A-V block in healthy older men is usually 3–4%, a prevalence severalfold greater than in young men (140). To reflect the age-associated slowing of A-V conduction, a value of 0.22 seconds has been proposed for the upper limit of normal P–R interval in persons over 50 years of age (140). Both cross-sectional and longitudinal studies have generally found no correlation between first-degree A-V block and cardiac disease (141) or mortality (142). QRS Complex Although the QRS duration shows no significant age relationship, the QRS axis shifts progressively leftward with age. In the database of 46,129 normals, there was a shift in the mean QRS axis from 568 to 88 between the third and ninth decades, with no gender difference (138). The corresponding lower normal limits shifted from –38 to –608. Thus, the prevalence of left-axis deviation of less than –308 increases dramatically with age, reaching 20% by the tenth decade (143). This leftward QRS axis shift may be largely due to the age-related increase in LV wall thickness (74,75). Longitudinal studies have failed to demonstrate any increase in cardiac morbidity or mortality associated with this isolated ECG finding (144,145). In patients with known organic heart disease, however, left or right bundle branch block (BBB) portends a worse CV prognosis if left axis deviation is present (146). Cross-sectional (147) and longitudinal (148) studies have demonstrated a decrease in R- and S-wave amplitudes with advancing age, evident by the fourth decade. At first glance,

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this decrease in QRS amplitude seems paradoxical, given the age-related increase in LV thickness. However, the surface ECG is influenced by extracardiac as well as cardiac factors. By increasing the distance between the heart and the chest wall, senile kyphosis and pulmonary hyperinflation in older individuals may contribute to a decrease of QRS voltage. Despite the age-related decline in mean QRS amplitude, the prevalence of electrocardiographic LV hypertrophy (LVH) increases with age (149), probably secondary to the high prevalence of hypertension, CAD, and degenerative aortic valvular disease in the elderly. Echocardiographic studies have demonstrated that the standard ECG is quite insensitive, although very specific, for anatomical LVH in older populations (150). In the Framingham study (149,150) and other older cohorts (123), ECG evidence of LVH was strongly related to the presence of hypertension and was a potent independent risk factor for future CV morbidity and mortality. Thus, the presence of ECG criteria for LVH in an older individual should normally trigger further diagnostic assessment, particularly echocardiography. Left and right BBB both increase in prevalence with age (152–154); nevertheless, these conduction defects should not be attributed to aging per se. In older populations, left BBB occurs only about half as often as right BBB. In contrast to its right-sided counterpart, left BBB is uncommon in the absence of CV disease (155). The prognosis of left BBB therefore reflects that of the underlying heart disease. Whereas left BBB portended a more ominous prognosis than right BBB in Framingham men, the two conduction defects had similar prognostic significance in women (152,153). Among 310 predominantly middle-aged individuals with BBB and no apparent heart disease, both left BBB and right BBB increased in prevalence with age, but neither was associated with increased total mortality over a 9.5-year mean follow-up (155). A nonspecific intraventricular conduction defect exceeding 120 milliseconds occurred in only 1.9% of Framingham participants aged 70 years and older and, like left BBB, was strongly associated with clinical heart disease (156). Complete right BBB was observed in 39 of 1142 men (3.4%) in the BLSA (157). Among the 24 individuals (mean age 64 years) without evidence of heart disease and for whom follow-up information was available, the incidence of angina, nonfatal myocardial infarction (MI), heart failure, advanced heart block, or cardiac death did not differ from those in age-matched controls over a mean observation period of 8.4 years. At long-term follow-up, maximal exercise capacity and maximal heart rate were similar to those of controls, although a higher prevalence of left-axis deviation was found in the group with right BBB (46% vs. 15%, respectively) (157). These findings suggest that right BBB in the absence of clinical heart disease is not rare in older men and reflects a primary abnormality of the cardiac conduction system. Women in the Framingham study demonstrated a lower prevalence of right BBB than men, but had a stronger association of this conduction defect with cardiomegaly and congestive heart failure (152). Q waves in two or more contiguous ECG leads are generally considered evidence of prior MI. In older, as in younger, populations, such Q waves are usually associated with clinical heart disease and increased cardiac mortality. Indeed, pathological Q waves may serve as the initial clue to the presence of CAD. Prior studies have shown that 25–30% or more of acute infarctions are clinically silent (158–160). The incidence of such “silent” infarctions increases strikingly with age. Aronow et al. (160) reported that 68% of infarctions were silent in a geriatric chronic care facility. Despite the absence of symptoms, these silent MI’s portend a long-term risk of mortality similar to their symptomatic counterparts. Among the elderly, Q waves commonly occur in the absence of CAD. A QS complex in leads 3 and a VF may occasionally result from marked left-axis deviation. A

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pattern of poor R-wave progression in leads V1 to V3 is a normal age trend, because of the decrease in the initial 20 milliseconds anterior QRS vector with age (140). Such a pattern may also result from obesity, chronic obstructive lung disease, and LVH, all of which are common in older populations. Repolarization Abnormalities involving the ST segment and T wave probably constitute the most prevalent age-associated findings on the ECG. In a study of 671 persons aged 70 years and older, nonspecific ST–T changes were the most common ECG abnormalities, occurring in 16% of individuals (154). In this sample and others, repolarization abnormalities were generally associated with clinical heart disease. Such an association may stem in part from the frequent use of digitalis and various antiarrhythmic drugs by elderly cardiac patients. Much of the reported increased risk attached to these nonspecific repolarization changes is undoubtedly due to the underlying heart disease that necessitated use of these cardiac medications. Even among clinically healthy older persons, however, minor ST-segment sagging or straightening is relatively common, although of questionable prognostic significance. A decrease in the T-wave amplitude with age begins by the fourth decade (140,147). The spatial T-wave vector shifts leftward with age in concert with the leftward shift in ORS axis. Obesity magnifies these changes in the T waves, especially in men (140). The isolated presence of flattened T waves, particularly in lead aVL, does not portend increased CV risk, at least in middle-aged samples (161). In contrast, definite T-wave inversion usually occurs in patients with organic heart disease and is associated with increased mortality. In the huge database of Mason et al. (138), the mean heart rate-corrected Q–T interval increased from 409 to 418 milliseconds in women and from 391 to 407 milliseconds in men between the third and the sixth decade. The prognostic significance of prolonged QT interval in apparently healthy older adults is controversial. Although no association between QTc prolongation and either sudden cardiac death or total mortality was found in the Framingham study (162), positive associations were reported in the Cardiovascular Health Study (CHS) (163) and the Zutphen (164) and Rotterdam (165) studies. In the latter study, a QTc >456 milliseconds in men and >470 milliseconds in women was associated with a 2.5fold increased risk of sudden death after adjustment for multiple CV risk factors (166). This risk was increased eightfold in persons younger than the mean age of 68 years, but only twofold in older individuals. Increased QT-interval dispersion, defined as the difference between the maximum and minimum QTc among the ECG leads, was also associated with a doubled risk of sudden death in this cohort (167). Table 3 summarizes those changes in resting ECG measurements thought to be secondary to normative aging. ARRHYTHMIAS An increase in the prevalence and complexity of both supraventricular and ventricular arrhythmias, whether detected by resting ECG, ambulatory monitoring, or exercise testing, is a hallmark of normal human aging. Atrial Arrhythmias Isolated premature atrial ectopic beats (AEB) appear on the resting ECG in 5–10% of individuals older than 60 years and are not generally associated with heart disease. Isolated AEB were detected in 6% of healthy BLSA volunteers older than 60 years at rest, in 39%

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Table 4 Arrhythmias on 24-Hour ECG in 1372 Ambulatory Persons
65 Years Old Arrhythmia

Women (%)

Men (%)

Gender differencea

Supraventricular Any
15 in any hr PSVT (
3 complexes) Atrial fibrillation or flutterb

97 18 50 3

97 28 48 3

No Yes No No

Ventricular Any
15 in any hr VT (
3 complexes) VT (>5 complexes)

76 14 4 0.3

89 25 13 0.2

Yes Yes Yes No

a

Defined by p < 0.05. Sustained or intermittent. Abbreviations: PSVT, paroxysmal supraventricular tachycardia; VT, ventricular tachycardia. Source: Adapted from Ref. 170. b

during exercise testing, and in 88% during ambulatory 24-hour monitoring (168). Such isolated AEB on ambulatory monitoring, even if frequent, were not predictive of increased cardiac risk in this sample over a 10-year mean follow-up period (169). Among 1372 predominantly healthy persons
65 years old in the CHS, isolated AEB were found in 97% and were frequent in 18% of women and 28% of men (Table 4) (170). Atrial Fibrillation Atrial fibrillation (AF) is found in approximately 3–4% of subjects over age 60 years (Table 4), a rate 10-fold higher than the general adult population (170,171); the prevalence in octogenarians approaches 10% (172). Chronic AF is most commonly due to CAD and hypertensive heart disease, mitral valvular disorders, thyrotoxicosis, and sick sinus syndrome. The association between hyperthyroidism and AF is observed almost exclusively in the elderly (173); this arrhythmia may be the sole clinical manifestation of so-called apathetic hyperthyroidism in geriatric patients. In the Framingham population, AF without identifiable cause, so-called lone AF, represented 17% of men and 6% of women with AF, with mean ages of 70.6 and 68.1 years, respectively (174). Individuals with lone AF suffered over four times as many strokes as those in sinus rhythm during long-term follow-up, although their rates of coronary events or congestive heart failure were not increased (174). Atrial flutter is a rare arrhythmia in any age group and is usually associated with organic heart disease. Several age-associated physiological changes contribute to the high prevalence of AF among the elderly. As noted above, left atrial size increases modestly with age, providing an augmented late diastolic filling rate that appears to compensate for the agerelated reduction in early filling. Among adults aged
65 years, in Olmstead County, Minnesota, who underwent clinically indicated echocardiography, both a larger left atrial volume and impaired early diastolic LV function were independent predictors of nonvalvular AF (175). In addition, both left and right atrial wavefront propagation velocities show strong inverse correlations with age, increasing the likelihood for intraatrial reentry to occur in older individuals (176).

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Figure 13 Risk of postoperative atrial fibrillation after cardiac surgery as a function of age and left atrial volume in 205 patients. Source: From Ref. 179.

Paroxysmal AF also increases strikingly with age. Among CHS participants in sinus rhythm, short runs of AF were seen in *3% of individuals during 24-hour ambulatory ECG monitoring (Table 4) (170). In a series of persons with paroxysmal AF, the number and duration of abnormal atrial electrograms recorded during sinus rhythm increased with age (177). The incidence of postoperative AF, a major cause of morbity and increased hospital costs, also rises steeply with age. Among 527 patients undergoing major elective thoracic surgery, age was the strongest predicter of postoperative AF; odds of this arrhythmia were increased 2.5-fold in persons
70 years old versus those <60 years (178). A recent study of 205 patients undergoing elective cardiac surgery demonstrated additive effects of age and left atrial volume on the seven-day incidence of postoperative AF (Fig. 13) (179). Paroxysmal Supraventricular Tachycardia Short bursts of paroxysmal supraventricular tachycardia (PSVT) on a resting ECG are found in 1–2% of normal individuals older than 65 years. Twenty-four-hour ambulatory monitoring studies have demonstrated short runs of PSVT (usually 3 to 5 beats) in 13–50% of clinically healthy older persons (Table 4) (168,170). Although the presence of nonsustained PSVT on ambulatory monitoring did not predict an increase in risk of future coronary events in BLSA participants, 2 of 13 individuals with PSVT later developed de novo AF, compared with only 1 of the 85 without PSVT (169). Exerciseinduced PSVT has been observed in 3.5% of over 3000 maximal treadmill tests on apparently healthy BLSA volunteers (180). The arrhythmia increased sharply with age, from 0% in the twenties to approximately 10% in the eighties (Fig. 14A); similar to PSVT on ambulatory ECG, the vast majority of these episodes were asymptomatic 3- to 5-beat salvos. Coronary risk factors and ECG or thallium scintigraphic evidence of ischemia occurred with similar prevalence in the 85 volunteers with exercise-induced PSVT as in age- and sex-matched controls. Of importance, the group with PSVT experienced no increase in subsequent coronary events over a 5.5-year mean follow-up period. However, 10% of the individuals with PSVT later developed a spontaneous atrial tachyarrhythmia compared with only 2% of the control group, analogous to the results of the ambulatory 24-hour ECG (180).

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Figure 14 Increased prevalence of exercise-induced cardiac arrhythmias with age during the initial maximal treadmill exercise test in BLSA volunteers free from clinical cardiac disease. The numbers above each bar represent the number of persons in each age decade by gender. (A) Prevalence of exercise-induced nonsustained SVT as a function of age and sex in 1383 apparently healthy individuals. The age-associated increase in SVT prevalence was more pronounced in men (p< 0.001) than in women (p ¼ 0.09). (B) Prevalence of frequent or repetitive ventricular ectopic beats in 1160 clinically healthy volunteers. A highly significant increase in prevalence was observed with age in men but not in women. Abbreviation: BLSA, Baltimore Longitudinal Study of Aging; SVT, supraventricular tachycardia. Source: (A) From Ref. 180 and (B) from Ref. 193.

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Ventricular Arrhythmias Both in unselected populations and in those clinically free of heart disease, an exponential increase in the prevalence of ventricular ectopic beats (VEB) occurs with advancing age. Pooled data from nearly 2500 ECGs from hospitalized patients older than 70 years revealed VEB in 8% (181). Among apparently healthy BLSA volunteers with a normal ST-segment response to treadmill exercise, isolated VEB occurred at rest in 8.6% of men over age 60 years compared with only 0.5% in those 20 to 40 years old (182). Of note, the prevalence of resting VEB was not age related in women. The prognostic significance of VEB detected on the resting ECG in the general elderly population is controversial. Significant increases in cardiac mortality among persons with VEB were observed in studies from Busselton (183) and Manitoba (184), with risk ratios of 3.3 and 2.4, respectively, compared with arrhythmia-free cohorts. The Framingham community, however, demonstrated no increase in the age-adjusted risk ratio for cardiac events (185). Data from the MRFIT (Multiple Risk Factor Intervention Trial) study suggest that the prognostic significance of resting VEB may vary according to age; asymptomatic white men under 50 years with frequent or complex VEB on a 2-minute resting rhythm strip suffered a 14-fold relative risk of sudden cardiac death, while in older men the risk was not significantly increased (186). Twenty-four-hour ambulatory ECG recordings have demonstrated the presence of VEB in 69–96% of asymptomatic elderly (169,170,187,188). Not only the prevalence but also the density and complexity of VEB increase with age. In the CHS, VEB were found in 82% of 1372 subjects aged 65 years and older, including 7% with 3- to 5-beat runs of nonsustained ventricular tachycardia (VT). The prevalence of all VEB forms was higher in men than in women (Table 4) (170). Among 50 individuals older than 80 years without clinical heart disease, VEB were observed in 96%, including multifocal VEB in 18%, couplets in 8%, and nonsustained VT in 2% (187). In 106 predominantly healthy patients aged 75 years and above, Camm et al. detected VEB in 69% (188); VEB were multiform in 22% and paired in 4% and occurred in short runs in 4%. Among 98 carefully screened asymptomatic BLSA participants older than 60 years, 35% had multiform VEB, 11% VEB couplets, and 4% short runs of VT on 24-hour monitoring (168). The prevalence of simple and complex VEB in all of these studies is much higher than in series of healthy younger volunteers. The prognostic importance of VEB detected on ambulatory monitoring, like those found on the resting ECG, is unclear. Over a 10-year mean follow-up period, 14 of the 98 older, carefully screened BLSA participants who underwent ambulatory ECG developed coronary events. The prevalence and complexity of VEB were virtually identical in the group that experienced an event and the group that did not (169). However, horizontal or slowly upsloping ST-segment depression on the ambulatory ECG predicted an increased risk of such events (169). In the series of Camm et al. (189), 92% of the five-year survivors who were initially free of VEB remained without VEB on the five-year followup recording. In contrast to the BLSA results, an almost doubled crude mortality was found among individuals with
10 VEB/hr versus those with fewer VEB. It should be noted that 83% of the Camm et al. volunteers were taking medications, including several patients with known heart disease. In a cohort of 456 Swedish men aged 68 years, frequent or complex VEB on 24-hour ECG were found in 35% of those without clinical coronary heart disease (CHD) and predicted increased risk of MI and CHD mortality over a 10.3-year mean follow-up (190). Exercise testing elicits a striking increase in the prevalence and complexity of VEB with advancing age similar to that seen on the ambulatory ECG. In apparently healthy

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BLSA volunteers, isolated VEB during or after maximal treadmill exercise increased in prevalence from 11% to 57% between the third and ninth decade (182). Although LV mass index and peak exercise systolic blood pressure were higher in subjects who developed exercise-induced VEB than in those who did not, by multivariate analysis only older age independently predicted the appearance of VEB (191). Asymptomatic exercise-induced runs of VT, all 6 beats in duration, were found in 4% of apparently healthy BLSA individuals aged 65 and older, a rate 25 times that of younger persons (192). Over a mean follow-up of about two years, however, none of these older volunteers with nonsustained VT during exercise testing developed angina, MI, syncope, or cardiac death. In a subsequent BLSA analysis, of 1160 clinically healthy individuals who underwent an average of 2.4 maximal treadmill exercise tests per individual, 80 developed frequent VEB (
10% of beats in any minute) or nonsustained VT on one or more tests (193). These 80 individuals were older than those free of such arrhythmias (64 vs. 50 years). Of note, the striking age-associated increase in occurrence of these complex exercise-induced VEB was observed only in men (Fig. 14B). The prevalence of coronary risk factors and exercise-induced ischemia by ECG and thallium scanning as well as the incidence of cardiac events (angina pectoris, nonfatal infarction, cardiac syncope, or cardiac death) was nearly identical in cases and controls matched for age and sex over a mean follow-up of 5.6 years without antiarrhythmic drug therapy (193). However, in a 23year follow-up of 6101 French men aged 42 to 53 years and initially free of clinical CV disease, frequent VEB during exercise predicted a 2.5-fold increased risk of CV death, independent of standard coronary risk factors (194). Thus, the available data available in older adults without apparent heart disease support a marked age-related increase in the prevalence and complexity of exercise-related VEB, at least in men; however, the prognosis conferred by frequent or repetitive VEB induced by exercise in such individuals is unclear. A factor of major importance in determining the prognostic significance of VEB in the elderly is the milieu in which they occur. For example, among 467 patients aged 62 to 101 years in a long-term care facility, complex VEB occurred during 24-hour ambulatory monitoring in 21% (195). In the subset without clinical heart disease, future coronary events developed in an identical 4% of those individuals with or without complex VEB; among patients with CAD, however, such events developed in 46% with complex VEB but only 23% of patients without them. A similar doubling of risk was seen in patients with hypertension, valvular disease, or cardiomyopathy who demonstrated complex VEB. Table 5 summarizes the effect of age on the prevalence of various cardiac arrhythmias and their relationship to mortality in apparently healthy older adults (196). Table 5 Relationship of Arrhythmias to Age and Mortality Arrhythmia Supraventricular ectopic beats Paroxysmal supraventricular tachycardia Atrial fibrillation (chronic) Ventricular ectopic beats Ventricular tachycardia (short runs) a

In healthy elderly.

Effect of age on prevalence

Effect on mortalitya

Increased Increased

None Probably none

Increased Increased Increased

Increased Probably none Probably none

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In summary, aging is associated with multiple ECG changes in persons without evidence of CV disease. Such changes include a blunted respiratory sinus arrhythmia, a mild P–R interval prolongation, a leftward shift of the QRS axis, and increased prevalence, density, and complexity of ectopic beats, both atrial and ventricular. Although these findings generally do not affect prognosis in clinically healthy older adults, other findings that become more prevalent with age, such as increased QRS voltage, Q waves, QT interval prolongation, and ST–T-wave abnormalities, are generally associated with increased CV risk. Abnormalities such as left BBB or AF are strongly predictive of future cardiac morbidity and mortality among older adults, even if asymptomatic. A guiding principle for the practitioner is that the prognosis associated with a given ECG abnormality in the elderly is more strongly related to the presence and severity of underlying CV disease than to the ECG finding itself. The views expressed in this chapter are those of the authors and do not necessarily represent those of the National Institutes of Health or the Department of Health and Human Services. REFERENCES 1. United States Bureau of the Census. //www.census.gov/population/www/estimates/popest. html. 2. Lakatta EG. Cardiovascular regulatory mechanisms in advanced age. Physiol Rev 1993; 73:13. 3. Virmani R, Avolio AP, Mergner WJ, et al. Effect of aging on aortic morphology in populations with high and low prevalence of hypertension and atherosclerosis. Comparison between occidental and Chinese communities. Am J Pathol 1991; 139:1119–1129. 4. Nagai Y, Metter EJ, Earley CJ, et al. Increased carotid artery intimal-medial thickness in asymptomatic older subjects with exercise-induced myocardial ischemia. Circulation 1998; 98:1504–1509. 5. O’Leary DH, Polak JF, Kronmal RA, et al. Carotid artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. Cardiovascular Health Study Collaborative Research Group. N Engl J Med 1999; 340:14–22. 6. Stary HC, Blankenhorn DH, Bleakley CA, et al. A definition of the intima of human arteries and its atherosclerosis-prone regions: a report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Circulation 1992; 85:391–405. 7. Spagnoli LG, Orlandi A, Mauriello A, et al. Aging and atherosclerosis in the rabbit. Distribution, prevalence, and morphology of atherosclerotic lesions. Atherosclerosis 1991; 89:11–24. 8. Clarkson TB. Nonhuman primate models of atherosclerosis. Lab Animal Sci 1998; 48:569–572. 9. Hodis HN, Mack WJ, LaBree L, et al. Reduction in carotid arterial wall thickness using lovastatin and dietary therapy. A randomized, controlled clinical trial. Ann Intern Med 1996; 124:548–556. 10. Heblad B, Wikstrand J, Janzon L, et al. Low-dose metoprolol CR/XL and fruvastatin slow progression of carotid intima-media thickness. Main results from the b-blocker cholesterollowering asymptomatic plaque study (BCAPS). Circulation 2001; 103:1721–1726. 11. Furberg CD, Adams HP, Applegate WB, et al. Effect of lovastatin on early carotid atherosclerosis and cardiovascular events. Asymptomatic Carotid Artery Progression Study (ACAPS) Research Group. Circulation 1994; 90:1679–1687. 12. Lonn EM, Yusuf S, Dzavik V, et al. Effects of ramipril and vitamin E on atherosclerosis. The study to evaluate carotid ultrasound changes in patients treated with ramipril and vitamin E (SECURE). For the SECURE Investigators. Circulation 2001; 103:919–925. 13. deGroot E, Jukema JW, van Swijndregt ADM, et al. B-mode ultrasound assessment of pravastatin treatment effect on carotid and femoral artery walls and its correlations with coronary arteriographic findings: a report of the regression growth evaluation statin study (REGRESS). J Am Coll Cardiol 1998; 31:1561–1567.

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Echocardiographic Measurements in Elderly Patients Without Clinical Heart Disease Julius M. Gardin St. John Hospital and Medical Center and Wayne State University, Detroit, Michigan, U.S.A.

Cheryl K. Nordstrom University of Michigan, Ann Arbor, Michigan, U.S.A.

INTRODUCTION The ability to image cardiac structures and to assess left ventricular (LV) function noninvasively has made echocardiography extremely useful in the evaluation of individuals with known or suspected heart disease. The noninvasive character of the ultrasound technique has made it particularly applicable to an older population (1,2). The goals of this chapter are to (1) discuss the effect of aging on LV systolic and diastolic function by M-mode and Doppler echocardiography and (2) present normative M-mode and Doppler echocardiographic measurement data that can serve as a basis for evaluating cardiac structure and function in elderly individuals. This chapter presents data derived from (1) Doppler measurements of aortic flow velocity, used to evaluate LV systolic performance at rest and during exercise, and (2) transmitral flow velocity measurements, used to assess LV diastolic function at rest. RELATIONSHIP OF AGE TO NORMAL M-MODE ECHOCARDIOGRAPHIC MEASUREMENTS To determine the relationship between age and M-mode echocardiographic measurements in normal subjects, we studied 136 adults (78 men and 58 women), aged 20 to 97 years, without evidence of cardiovascular disease (CVD) (3). These subjects all underwent a comprehensive medical history and physical examination, chest roentgenography, electrocardiography, and M-mode echocardiography. In no subject did this evaluation reveal the presence of heart disease, hypertension, other serious illness, or obesity. 45

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Figure 1 Echocardiographic recording of the left ventricle showing parameters of left ventricular muscle mass and percentage fractional shortening. Abbreviations: VSd, interventricular septal thickness measured during diastole; LVTDd, left ventricular transverse dimension measured during diastole; LVTDs, left ventricular transverse dimension measured during systole. Source: From Ref. 71.

Furthermore, all subjects had a normal electrocardiogram (ECG), normal chest film, and no evidence of mitral valve prolapse or pericardial effusion on M-mode echocardiogram. M-mode echocardiography was performed in the left lateral decubitus position, and the following measurements were made: LV internal dimensions at end diastole (LVIDd) and end systole (LVIDs); ventricular septal (VSd) and posterobasal LV free-wall thickness (LVPWd) at end diastole; aortic root and left atrial dimensions; and mitral valve E–F slope, which corresponds to the rate of early diastolic closure of the anterior mitral valve leaflet (Fig. 1). In addition, LV mass, ejection fraction, and fractional shortening were derived from the following formulas (4): LV mass ¼ ½ð1:05ÞðLVIDd þ VSd þ LVPWd Þ3  ðLVIDd Þ3  LV ejection fraction ¼

ðLVIDd Þ3  ðLVIDs Þ3

LV % fractional shortening ¼

ðLVIDd Þ3

 100%

ðLVIDd Þ  ðLVIDs Þ  100% ðLVIDd Þ

ð1Þ ð2Þ

ð3Þ

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In the absence of localized disorders of LV function like those that may be present in coronary artery disease, M-mode echocardiographic estimates have been reported to correlate well with two-dimensional echocardiographic and angiographic measurements of LV volume and ejection fraction (4). Also, under these conditions, LV percentage fractional shortening gives information similar to that obtained from LV ejection fraction. Although ejection fraction does not perfectly characterize the functional state of the LV, this measurement is accepted as providing an overall assessment of pump performance. Furthermore, ejection fraction is thought to be a more sensitive measurement of myocardial contractile state than either cardiac output or LV end-diastolic pressure. Echocardiographic measurements were analyzed for the influence of age, sex, and body surface area (BSA). When the data for each echocardiographic parameter were analyzed separately for men and women as a function of BSA, statistically significant differences between men and women were found for three parameters: (1) ventricular septal thickness, (2) posterobasal free-wall thickness, and (3) estimated LV mass. However, since the sex differences for these three parameters were relatively small (range, 6.2–7.2%), we chose for the sake of simplicity to combine data for men and women in our calculation of regression equations and prediction intervals (3,5,6). When patients were subdivided into six age groups, progressive changes were found in mean normal values for various M-mode echocardiographic parameters (Fig. 2). Specifically, when the older group (over 70 years) was compared with the youngest group (21–30 years), significant (p < 0.01) increases in aortic root (22%) and left atrial (16%) dimensions, ventricular septal (20%) and LV free-wall (18%) thicknesses, and estimated LV mass (15%) were noted (3,5,6). In addition, a significant (p < 0.01) decrease in mean mitral E–F slope (43%) and slight decreases in mean LV systolic and diastolic internal dimensions (5% and 6%, respectively; p < 0.05) were noted. LV ejection fraction and

Figure 2 Percentage change in M-mode echocardiographic measurements in five older age groups compared with the 21- to 30-year age group. Data are displayed for AO, LA, LVWT, EJ FRACT, LVIDd, and mitral E–F slope. Abbreviations: AO, aortic root dimension; LA, left atrial dimension; LVWT, left ventricular posterobasal free-wall thickness in diastole; EJ FRACT, LV ejection fraction; LVIDd, LV internal dimension in diastole.

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percentage fractional shortening were independent of age. These data were used to derive regression equations related to both age and BSA. The regression equations can be used to calculate mean normal values and 95% prediction intervals for echocardiographic measurements in adults. We analyzed our data according to the general regression equation Echo parameter ¼ BðBSAÞ þ A  C; where A represents the intercept, B represents a slope unique for each parameter, and C represents the width of the 95% prediction interval; that is, the interval into which, with 95% confidence, a new normal observation would be expected to fall (3). When subjects were subdivided into six age groups, the slope of the regression relationship was found to be independent of age for every parameter (p > 0.05), whereas the intercept showed significant variation with age for every parameter (p < 0.05). Therefore, we assumed that the intercept A, but not the slope B, was influenced by age and that the width of the 95% prediction interval C was constant and not appreciably influenced by age or BSA. The values of A derived from our data for each age group are given in Table 1, which also includes the values of B and C for each parameter (3). Figures 3 through 7 depict the relationships between age and aortic root dimension, left atrial dimension, LV diastolic and systolic dimension, LV posterior wall thickness, and LV mass. For each figure, the regression equations in Table 1 have been utilized to adjust the values to three representative BSA values (1.4, 1.8, and 2.2 m2) (3). Our echocardiographic findings are compatible with information derived from previous studies using other methods. Roberts and Perloff noted that hearts of older individuals studied at necropsy appear to have smaller ventricular chambers and thicker walls than those of their younger counterparts (7). Although the magnitude of the decrease was small, we also noted that the internal dimensions of the LV decreased as age increased. We also noted progressive increases in the thickness of the ventricular septum and the LV free wall with increasing age. The magnitudes and rates of increase were similar for the septum and free wall, so that there was no change in the septum–free-wall

Table 1 Regression Equations of Echocardiography Measurements Vs. Age Intercepts (age dependent) Equation LVIDd LVIDs Septum LVPW LV mass Ao LA E–F slope

¼ ¼ ¼ ¼ ¼ ¼ ¼ ¼

6.94 4.24 2.53 2.18 124 8.31 9.98 20.1

(BSA) (BSA) (BSA) (BSA) (BSA) (BSA) (BSA) (BSA)

þ þ þ þ þ þ þ þ

21–30

31–40

41–50

51–60

61–70

70

Prediction interval

35.5 22.4 5.27 6.11 9.87 12.3 16.3 99.9

36.2 22.6 5.47 6.02 1.98 13.1 16.7 90.2

34.4 21.5 6.27 6.94 8.56 14.7 17.6 78.3

34.1 21.1 6.53 6.97 10.8 15.6 18.0 66.6

34.8 21.7 6.84 7.34 26.8 16.4 19.3 62.2

32.7 20.8 7.20 7.81 22.2 18.5 21.7 43.5

5.60 5.81 1.75 1.43 57.6 5.76 7.01 62.2

Abbreviations: Ao, aortic root dimension; BSA, body surface area; LA, left atrial dimension; LVID, left ventricular internal dimension; d, diastolic; s, systolic. Source: From Ref. 3.

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Figure 3 Aortic root dimension in late diastole in millimeters versus age in years. In Figures 3 through 7, the mean value for each age group is depicted by a circle plotted at the mean age in the age group. The bracketed and shaded area on either side of the circle represents the 95% prediction interval for normal values for a subject with a BSA of 1.8 m2. The 95% prediction intervals are also shown for subjects with BSA values of 1.4 m2 (dotted lines) and 2.2 m2 (solid lines). Abbreviation: BSA, body surface area. Source: From Ref. 3.

Figure 4 Left atrial dimension in late diastole in millimeters versus age in years. For each age group, the mean and 95% prediction interval for normal values are depicted. Source: From Ref. 3.

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Figure 5 Left ventricular end-diastolic and end-systolic dimensions in millimeters versus age in years. For each age group, the mean and 95% prediction interval for normal values are depicted. Source: From Ref. 3.

Figure 6 Left ventricular posterior wall thickness in late diastole in millimeters versus age in years. For each age group, the mean and 95% prediction interval for normal values are depicted. Source: From Ref. 3.

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Figure 7 Estimated left ventricular mass in grams versus age in years. The mean and 95% prediction interval are depicted for each age group. Source: From Ref. 3.

ratio with increasing age. Estimated LV mass showed a small but progressive increase from the 21- to 30-year age group to the over 70 age group. This increase reflected an increase in wall thickness that was relatively greater than the decrease in LV diastolic dimension. Since the mean systolic and diastolic blood pressures varied by less than 15 mmHg among the six age groups, we could not ascribe the increased wall thickness or mass observed in our subjects solely to a change in basal arterial blood pressure with aging. Krovetz reviewed several published reports of measurements of aortic valve annulus size made at necropsy (8). When aortic annulus size was corrected for BSA, progressive increases with age were noted in both men and women over 20 years of age. We noted similar increases in aortic root dimensions as measured by echocardiography, a finding confirmed by Demir and Acarturk (9). These investigators found that men had greater aortic root dimensions than women (p < 0.001). Interestingly, they also noted correlations of aortic root dimension with LV mass in both men and women, but no correlation with LV internal dimensions or ejection fraction. The progressive increase in left atrial dimension with increasing age in our normal adult subjects was previously noted by Roberts and Perloff at necropsy (7). It is important to take this age-related change into account when using echocardiographic measurements of left atrial dimension to make quantitative statements about the effects of various disease states [e.g., hypertension or valvular or coronary heart disease (CHD)]. Various investigators have reported functional changes with age in mitral valve motion consistent with our findings of decreased E–F slope (10). Factors postulated to explain this decrease in the rate of early diastolic closure of the anterior mitral valve leaflet have included sclerosis of the mitral leaflets and/or decreased compliance of the LV (10).

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In our studies, LV ejection fraction and percentage fractional shortening did not change appreciably as age increased from 20 to 97 years. These findings are consistent with several previous studies (11,12), including one in which LV function was assessed with radionuclide cineangiography (11). If the LV internal dimension at end diastole is mildly reduced in older subjects, while ejection fraction and heart rate are unchanged, stroke volume and cardiac output at rest are expected to diminish slightly with advancing age. Data confirming this inference have been reported using a dye-dilution technique (13,14). Our findings relating changes in echocardiographic parameters to increasing age are generally in agreement with findings reported by Gerstenblith et al. (15). The major difference is that we found a slight but significant decrease in LV systolic and diastolic internal dimensions with increasing age, whereas Gerstenblith and associates found no change. Importantly, women were not included in their study population, nor did they report measurements of left atrial dimension or LV mass. More recently, Shub et al. found increased LV mass to be associated with increasing age among women, but not among men (16). This variation may have been due to increasing body mass index with age among women only. Findings from the Framingham Heart Study showed that age, height, systolic blood pressure, and body mass index were significant independent predictors of LV mass in 2226 men and 2746 women aged 17 to 90 years (17). However, when persons with (1) evidence of cardiopulmonary disease by history, physical examination, ECG, chest X ray, or echocardiogram; (2) systemic arterial blood pressure of at least 140/90 mmHg at the time of echocardiography; (3) use of prescription medications for cardiopulmonary disease; or (4) body weight 20% above or below the midpoint of recommended weight for height were excluded from the analyses, age was no longer a significant correlate of LV mass/height among 345 men and 517 women aged 20 to 79 years (18). These disparate findings suggest that increases in LV mass associated with age are likely confounded by risk factors that are associated with age, specifically obesity, hypertension, and clinically manifest cardiopulmonary disease. Although it is highly likely that the echocardiographic changes reported in the different age groups are related to the aging process, longitudinal studies are needed to document these changes in serial studies in the same patient. Nonetheless, it is clear that normal echocardiographic values corrected for both age and BSA (or another measure of body size) should be used when evaluating adult patients suspected of having heart disease. RELATIONSHIP OF AGE TO LV SYSTOLIC PERFORMANCE AS MEASURED BY DOPPLER AORTIC FLOW VELOCITY PARAMETERS Doppler flow velocity measurements in the aorta have been shown to be useful in differentiating normal subjects from those with LV dysfunction (19,20). For example, patients with dilated cardiomyopathy demonstrate aortic peak flow velocities, flow velocity integrals, and average accelerations that are markedly reduced compared with those in normal subjects (Fig. 8) (19). Furthermore, in patients with heart failure receiving vasodilator therapy, changes in Doppler aortic peak flow velocity and flow velocity integral have been shown to be useful in estimating changes in systemic vascular resistance and stroke volume, respectively (20). We evaluated the relationship between age and Doppler aortic flow velocity measurements in 97 adults (45 men and 52 women, aged 21–78 years) without clinical

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Figure 8 Doppler aortic and pulmonary flow velocity recording from a normal subject. Measurements include PFV in cm/sec; ET in ms; AT in ms; and average acceleration in cm/sec2 (calculated by dividing PFV by AT). The aortic flow velocity integral, or area under the flow velocity curve in cm, was also estimated. Abbreviations: PFV, peak flow velocity; ET, ejection time; AT, acceleration time. Source: From Ref. 17.

evidence of cardiac disease (21). No subject had a history of hypertension or CVD, and all had a normal cardiac examination, ECG, chest X-ray, and M-mode and two-dimensional echocardiogram. Figure 8 demonstrates an aortic flow velocity recording from a normal subject (21,22). Peak flow velocity was measured in centimeters per second at the midpoint of the darkest area of the spectrum at the time of maximum flow velocity. Ejection time (ET) was measured in milliseconds from the onset of the systolic flow velocity curve to the time the curve crossed the zero-flow line at end systole. Aortic flow velocity integral (centimeters), which represents the area under the flow velocity curve, was estimated by the following formula (20): Flow velocity integral ¼ 0:5  peak flow velocity  ET Multiple linear regression analysis revealed that age was significantly correlated with aortic peak flow velocity, average acceleration, and flow velocity integral (all p < 0.001) (22). Figure 9 depicts the relationship between aortic peak flow velocity and age. The two parameters were related by the following regression equation: Aortic peak flow velocity ¼ 0:6ðageÞ þ 110 ðr ¼ 0:54; p ¼ :001Þ Aortic peak flow velocity was significantly lower in the 61- to 70-year age decade (mean SD ¼ 93  11 cm/sec) than in the younger age group. (22). The correlation of aortic peak flow velocity with age remained significant (p < 0.001) after division of peak flow

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Figure 9 Relationship between aortic peak flow velocity (cm/sec) and age (years) in 80 subjects. The solid line represents the line of regression. Note the negative slope of the relationship between the two parameters (r ¼ 0.54). Aortic PFV is significantly lower in the 60- to 70-year age group than in the 21- 30-year age group (p < 0.001). Abbreviation: PFV, peak flow velocity. Source: From Ref. 18.

velocity by the square root of the R–R interval. More recently, Turkish investigators have also noted that aortic blood flow velocity was related to age (p < 0.001) in both men and women (9). Figure 10 depicts the relationship between aortic flow velocity integral and age. Note the significantly lower (p < 0.001) aortic flow velocity integral in the 61- to 70-year age decade (mean  SD ¼ 9.5  2.3 cm) compared with the 21- to 30-year age decade (13.8  2.1 cm). Aortic flow velocity integral and age are related by the following regression equation (22): Aortic flow velocity integral ¼ 0:09ðageÞ þ 16:5ðr ¼ 0:44; p < :001Þ The correlation with age remained significant (p < 0.01) after correction of aortic flow velocity integral for the square root of the R–R interval. The decreases in aortic peak flow velocity and flow velocity integral noted with increasing age are probably due, at least in part, to the increases in aortic root diameter noted with aging (3,5,8,15). It has previously been shown that resting stroke volume (3,5) and cardiac output (23) do not change significantly with aging. Since Doppler stroke volume can be estimated by multiplying the aortic flow velocity integral by the aortic root area, it follows that a decrease in flow velocity integral must be accompanied by an increase in aortic root area (and diameter) to maintain a constant stroke volume. Furthermore, since the aortic flow velocity integral is approximately equal to 1/2(peak flow velocity)  (ejection time) (20), and since aortic ejection time did not change with aging in this study, it follows that aortic peak flow velocity decreases with aging. We found no significant differences in Doppler aortic flow velocity measurements between men and women of the same age. Furthermore, there was no significant

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Figure 10 Relationship between aortic flow velocity integral (cm) and age (years). Note the significantly lower flow velocity integral in the 61- to 70-year age group than in the 21- to 30-year age group (p < 0.001). Source: From Ref. 18.

relationship between BSA or blood pressure and any of the aortic flow velocity parameters in this group of normal subjects (22). RELATIONSHIP OF AGE TO LV SYSTOLIC PERFORMANCE WITH UPRIGHT EXERCISE AS MEASURED BY DOPPLER AORTIC FLOW VELOCITY RECORDING DURING TREADMILL TESTING To evaluate the effect of upright exercise on aortic peak flow velocity and acceleration, 60 normal subjects, aged 15 to 74 years, were evaluated by continuous-wave Doppler during treadmill stress testing using the Bruce protocol (24). Subjects were divided into three age groups, each with 20 subjects: group I, 21  4 years (mean  SD); group II, 36  5 years; and group III, 58  7 years. Periodic measurements of heart rate, blood pressure, and Doppler blood flow velocity and acceleration were made before, during, and after exercise. Continuous-wave Doppler measurements were recorded from the suprasternal notch. The relationship between Doppler aortic measurements and age, gender, heart rate, and blood pressure responses during exercise were evaluated. Age alone was significantly related (inversely) to immediate postexercise Doppler aortic peak blood flow velocity (group I, 1.1  0.2; group II, 1.0  0.2; and group III, 0.8  0.2 m/sec, respectively; p < .01) and peak acceleration (group I, 55  15; group II, 46  11; and group III, 36  9 m/sec2; p < .05) (Figs. 11 and 12). Gender, heart rate, and blood pressure changes during exercise, as well as exercise preconditioning, had no significant effect on these aortic flow characteristics. These findings suggest that age is an important factor influencing aortic peak blood flow velocity and acceleration with exercise, as well as at rest. These changes in peak

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Figure 11 Doppler peak aortic blood flow velocity measurements before, during, and immediately after exercise. Data are shown as the mean for 20 subjects in each of the three groups, except as noted by n value in exercise stages III and IV. Abbreviations: Su, supine; St, standing; PO, immediate postexercise; P5, 5 minutes after exercise. Source: From Ref. 20.

Figure 12 Doppler peak acceleration measurements before, during, and immediately after exercise. Abbreviations and data display are as in Figure 11. Source: From Ref. 20.

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velocity and acceleration with exercise may reflect, in part, changes in exercise LV function with age. Earlier studies (25–27) showed close correlations between these flow parameters and muscle contractility. However, alterations in aortic configuration, size, and compliance, as well as impedance (afterload), likely affect these Doppler parameters to a significant degree. Importantly, these age-dependent changes must be taken into account when using Doppler-determined peak velocity and acceleration in evaluating LV performance.

RELATIONSHIP OF AGE TO GLOBAL LV DIASTOLIC FUNCTION AT REST AS EVALUATED BY DOPPLER TRANSMITRAL FLOW VELOCITY MEASUREMENTS Although LV systolic function is generally maintained with aging in healthy subjects (23), alterations in diastolic function are known to occur with “normal” aging (28,29). We evaluated the relationship between age and pulsed Doppler transmitral flow velocity measurements in 66 adult men and women, aged 21 to 78 years, without a history of hypertension or CVD (29). Measurements of early and late diastolic transmitral peak flow (filling) velocities, flow times, and flow velocity integrals, and early diastolic flow acceleration and deceleration were made at the level of the mitral leaflet tips. As shown in Figure 13, transmitral peak flow velocities in centimeters per second were measured in early and late diastole (i.e., at the time of atrial systole) at the midpoint of the darkest portion of the spectrum at the time of peak flow velocity. Differences in Doppler transmitral flow velocity patterns between 30-year-old and 63-year-old normal adults are depicted in Figure 14 (29). Mitral peak flow velocity in early diastole (PFVE) was significantly lower (p < 0.01) in the 61- to 70-year age decade (45  10 cm/sec) than in the 21- to 30-year age decade (66  11 cm/sec) (Fig. 15). Mitral peak flow velocity in late diastole (PFVA) was significantly higher (p < .05) in the 61- to 70-year age decade (55  11 cm/sec) than in the 21- to 30-year age decade (41  7 cm/ sec) (Fig 16). Mitral A/E ratio (i.e., PFVA/PFVE) was significantly higher (p < 0.01) in the oldest (1.2  0.3) than in the youngest (0.6  0.1) age group (Fig. 17). Early diastolic flow time increased with age (r ¼ 0.36; p < 0.001), whereas the rate of early diastolic deceleration decreased with age (r ¼ 0.59; p < 0.001). The results of this study demonstrate that aging is associated with progressive decreases in early diastolic transmitral peak flow velocity and early diastolic deceleration and progressive increases in late diastolic transmitral peak flow velocity and the ratio of late to early diastolic peak flow velocities. These findings are similar to those reported by Miyatake and associates (28). Evidence that the decrease in early diastolic transmitral peak flow velocity is related to impaired early diastolic LV filling has been provided by several studies. Dabestani et al. (30) showed in 10 patients who underwent both Doppler mitral flow velocity recordings and videodensitometric analysis of LV filling from digital subtraction left ventriculograms that the percentage of total filling completed by mid-diastole was directly related to the early diastolic peak flow velocity measured by Doppler. These findings suggest that Doppler measurements of peak flow velocity in early diastole are related to the rate of ventricular filling. Rokey et al. (31) also reported a significant correlation between early diastolic transmitral peak flow velocity and angiographic peak filling rate (r ¼ 0.64). They noted even better correlations between Doppler echocardiographic and angiographic peak filling rates (r ¼ 0.87).

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Figure 13 Normal flow velocity recording at the level of the mitral valve from the apical fourchamber view depicting the method for making Doppler measurements. Mitral PFVE and PFVA were measured (cm/sec) at the midpoint of the darkest portion of the spectrum at the time of the maximal flow velocity in early and late diastole, respectively. EDFT, ADFT, and EFDFT were measured as noted. Abbreviations: PFVE, peak flow velocity in early diastole; PFVA, peak flow velocity in late diastole; EDFT, early diastolic flow time; ADFT, late diastolic flow time; EFDFT, early diastolic deceleration time. Source: From Ref. 25.

Miyatake et al. (28) postulated that the increase in late diastolic peak transmitral flow velocity with aging reflects an augmentation of ventricular filling by atrial contraction that compensates for decreased early diastolic ventricular filling. Our study demonstrated not only age-related increases in late diastolic peak flow velocity, but also in late diastolic flow time and flow velocity integral (29). These findings provide further evidence for an age-related increase in the contribution of atrial systole to ventricular filling.

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Figure 14 Doppler mitral valve flow velocity recordings from a younger normal subject, age 30 (left), and from an older normal subject, age 63 (right). Note that the peak flow velocity in early diastole is lower and the late diastolic peak flow velocity is higher in the older subject than in the younger normal subject. Source: From Ref. 25.

Figure 15 Data for mitral PFVE (cm/sec) is displayed on the vertical axis versus age in years on the horizontal axis (n ¼ 66). Note the negative slope of the regression equation PFVE ¼ 0.52 (age) þ 79. The correlation coefficient r ¼ 0.55. Abbreviation: PFVE, peak flow velocity in early diastole. Source: From Ref. 25.

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Figure 16 Data for mitral PFVA (cm/sec) is displayed versus age in years (n ¼ 66). Note the positive slope of the relationship, mitral PFVA ¼ 0.39 (age) þ 27. Abbreviation: PFVA, peak flow velocity in late diastole. Source: From Ref. 25.

Figure 17 Data for mitral A/E ratio is depicted versus age in years. Note the positive slope of the relationship, mitral A/E ratio ¼ 0.016 (age) þ 0.13. Source: From Ref. 25.

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Figure 18 Natural history of LV filling. Source: From Ref. 34.

It may be that the position of the sample volume (tips of the leaflets or at the annulus) affects the relationship between age and diastolic function. Mantero et al. showed that the E-wave peak velocity at the mitral annulus was more strongly correlated with age than the velocity obtained at the tips of the mitral leaflets among 288 normal subjects aged 20 to 80 years (32). However, A-wave peak velocity at the leaflet tips was more strongly related to age than at the annulus. Similar results were found for the partial integrals of the E and A waves. We have previously shown that peak E- and A-wave velocities are both significantly higher (by about 20%) when measured at the leaflet tips than at the annulus (33). It is now well-established that pulsed Doppler recordings of pulmonary venous flow patterns can be useful in evaluating LV diastolic function and in classifying LV diastolic dysfunction into stages (e.g., abnormal relaxation, “pseudonormal,” and “restrictive filling”). However, in using pulmonary venous flow patterns, it is important to appreciate that these flow patterns may also be dependent on age in healthy subjects (Fig. 18) (34). Gentile et al. reported significant correlations between age and peak systolic flow velocity (r ¼ 0.5; p < 0.001) and its integral (r ¼ 0.5; p < 0.001), and peak diastolic flow velocity (r ¼ 0.6; p < 0.001) and its integral (r ¼ 0.44; p < 0.001), but not the atrial reversal wave (r ¼ 0.1; p > 0.05) among 143 normal subjects aged 20 to 80 years(35). Among 85 of 117 healthy volunteers with adequate tracings, Klein et al. found that those aged 50 years and older had increased pulmonary venous peak systolic flow velocity (71  9 vs. 48  9 cm/sec; p < 0.01), decreased diastolic flow velocity (38  9 vs. 50  10 cm/sec; p < 0.01), and increased peak atrial reversal flow velocity (23  4 vs. 19  4 cm/s; p < 0.01) compared with those younger than 50 years (36). Klein et al. later reported that the difference in duration of pulmonary venous atrial flow reversal and transmitral A-wave flow, previously related to LV end-diastolic pressure among patients with heart disease (37), was unrelated to aging in 72 healthy volunteers aged 23 to 84 years (r ¼ 0.16) (38). RELATIONSHIP OF AGE TO SYSTOLIC AND DIASTOLIC MYOCARDIAL FUNCTION AS EVALUATED BY TISSUE DOPPLER VELOCITY, STRAIN, AND STRAIN RATE Newer applications of pulsed Doppler have allowed assessment of regional myocardial function in systole and diastole. These applications are based on recording pulsed tissue Doppler velocity, strain, and strain rate and displaying the tissue Doppler information in a gray-scale or color format.

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Table 2 Early Diastolic, Late Diastolic, and Systolic Myocardial Velocities (by Myocardial Layer) Vs Age Group 18–25 yr (n ¼ 9)

26–45 yr (n ¼ 23)

Early diastole Peak endocardial 13.85  3.19 13.58  2.89 ED velocity Peak mesocardial 9.71  2.73 10.29  3.00 ED velocity 6.41  2.16 7.05  2.55 Peak epicardial ED velocity Peak ED MVG 11.01  2.34 9.72  1.90 Late diastole Peak endocardial LD velocity Peak mesocardial LD velocity Peak epicardial LD velocity Peak LD MVG Systole Peak endocardial S velocity Peak mesocardial S velocity Peak epicardial S velocity Peak S MVG

46–65 yr (n ¼ 22)

66–94 yr (n ¼ 13)

p

9.25  1.57

6.06  1.91

0.0005

7.47  1.88

4.98  1.33

0.0005

4.93  1.50

4.02  1.16

0.001

6.58  2.35

3.46  1.33

0.0005

2.16  1.46

2.85  1.46

4.37  1.71

5.95  2.74

0.0005

1.71  1.40

2.34  1.40

3.62  1.61

5.32  2.41

0.0005

1.53  1.23

1.73  1.32

2.60  1.28

4.23  2.06

0.0005

1.79  0.95

2.41  1.13

3.70  1.18

3.86  1.31

0.0005

5.71  1.19

5.49  1.26

4.87  1.42

5.03  1.42

0.3

4.73  1.06

4.83  1.29

4.45  1.34

4.30  1.13

0.5

3.32  0.89

3.61  1.05

3.35  1.11

3.50  1.23

0.8

4.61  1.05

4.30  1.49

3.50  1.23

3.8  1.82

0.2

Abbreviations: ED, early diastole; LD, late diastole; S, systole; MVG, myocardial velocity gradient. In the original table, “Early diastole” was referred to as “Protodiastole” and “Late diastole” as “Telediastole.” Results are expressed as mean  standard deviation. Source: From Ref. 40.

Tissue Doppler Velocity Color M-mode tissue Doppler imaging is an accurate method to assess the nonuniformity of transmural myocardial velocities and can be used for evaluating the impact of age on the different myocardial layers (39). As shown in Table 2, (40) the distribution of myocardial velocity across the myocardium is asymmetrical, with higher velocities in the subendocardium compared with the subepicardium. Moreover, this observation holds true for peak systolic, peak early diastolic, and peak late diastolic myocardial velocity. These data have been confirmed by myocardial velocity gradient curves across a broad age range. Sabbah et al. (41) reported that the maximal rate of systolic thickening of the total ventricular wall was higher than the maximal rate of systolic thickening of the epicardium. A previous report from Palka and associates, who used tissue Doppler myocardial velocities to study healthy subjects, also concluded that the subendocardium moves faster than the subepicardium during LV rapid filling (42). Several possible explanations for this phenomenon have been suggested. Models of LV wall mechanics have demonstrated that the orientation of cardiac fibers, which is heterogeneous in the normal heart, determines the distribution of fiber strain during ejection (43). Greater dimensional changes in the subendocardium during systole are also

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consistent with predictions based on geometric constraints in a model of concentric cylinders, and are due to the incompressibility of the myocardium (44). In experimental models, the maximal rate of thinning of the total wall during early diastole was significantly greater than the maximal rate of thinning of the epicardial portion (45). It has been suggested that early diastolic mitral velocities reflect myocardial relaxation, which is an active, energy-consuming process (46). The nonuniform distribution of velocities during early diastole could be explained by a more active role played by the subendocardial and mesocardial layers in myocardial relaxation. Table 2 (40) demonstrates that in all three myocardial layers, early diastolic mitral velocity decreases significantly with age. However, the impact of age on peak subendocardial velocity is greater than on the other more external myocardial layers (40). The relationship between age and relaxation of the normal myocardium is well known. Studies in isolated muscle preparations have demonstrated prolonged relaxation in aged rats (47). A progressive prolongation of myocardial relaxation also occurs in the human heart with normal aging (48). Furthermore, experimental studies in aging animals by Anversa and coworkers have demonstrated that progressive myocardial cell loss and replacement fibrosis take place mainly in the subendocardium of the LV (49). Thus, a wider extent of damage in the subendocardium with aging could explain a greater loss of its relaxation capability compared with the mesocardial and epicardial layers. Late diastolic peak velocities increase progressively and similarly with age in all of the myocardial layers (40). It is postulated that the different behavior of age-related changes in late diastole compared to early diastole is related to the physiologic differences existing between these two periods. Specifically, late diastolic mitral velocities seem to be more related to atrial contraction than to an active phenomenon (such as relaxation) in the LV (50). For this reason, age-related changes in the subendocardium, which could be critical in early diastole, do not appear to be as relevant in late diastole. Of interest, increasing age does not appear to have a significant effect on systolic velocity in any of the three myocardial layers (Table 2). Yamada and associates (51) also found a moderate inverse correlation between age and early diastolic myocardial velocity recorded in both the mid-ventricular septum and mid-LV posterior wall myocardium (range of r ¼ 0.51 to 0.61, all p values < 0.0001). This finding was true whether the myocardial velocities were recorded from the long or short axis view. In contrast, Yamada et al. found that late diastolic (peak atrial systolic) velocities along both long and short axes correlated directly with age (range of r ¼ 0.53 to 0.65, all p < 0.0001). Of interest, Onose and associates (52) reported that the peak velocity of the first systolic wave in the LV posterior wall, recorded by tissue Doppler from the long-axis direction (in the apical long-axis view), correlated inversely with age (p < 0.0001), but did not correlate significantly with the first derivative of the LV pressure (dP/dt) recorded at cardiac catheterization. The authors concluded that these results suggest that shortening of the longitudinal myocardial fibers in early systole is impaired with increased age in healthy individuals. They further postulated that this impairment results in insufficient spherical shape change in the LV cavity, although global LV pump function and myocardial contractility are apparently maintained (52). Similarly, in 118 healthy individuals (age range, 20–90 years), Nikitin et al. (53) used transmitral pulsed Doppler and color-coded myocardial tissue Doppler to assess LV relaxation and longitudinal LV function. These investigators also noted that systolic and early diastolic peak mitral annular velocities decreased (p < 0.0001), while late diastolic (atrial) myocardial velocity increased (p ¼ 0.0002) in older compared to younger subjects. (Table 3) (53). The authors concluded that although global LV systolic function is preserved with age, the velocity of

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Table 3 Systolic and Early and Late Diastolic Mitral Annular Velocities in Older Age Subgroups 60–69 yr (n ¼ 22) Sm (cm/sec) Em (cm/sec) Am (cm/sec) Em/Am ratio

5.44 5.49 6.68 0.84

   

1.06* 1.60*** 1.15 0.26***

70–79 yr (n ¼ 23) 5.28 4.45 7.12 0.64

   

1.11*** 1.39*** 1.18*** 0.20

80 yr (n ¼ 16) 4.15 3.09 6.04 0.53

   

0.79 1.1 1.48 0.25

*p < 0.05 between groups 1 and 2, ***p < 0.05 between groups 2 and 3. Abbreviations: Sm, peak systolic mitral annular velocity; Em, peak early diastolic mitral annular velocity; Am, peak late diastolic annular velocity. Source: From Ref. 53.

long-axis systolic myocardial shortening is depressed in older individuals, indicating a selective impairment of the longitudinal component of systolic contraction. Atrial mechanical function was assessed directly by Doppler tissue imaging in 131 healthy control subjects by Zhang et al. (54) These workers used echocardiography with color-coded tissue Doppler imaging to study the left atrial and right atrial free wall and intra-atrial septum, and found that peak atrial contraction velocity in the left atrium was higher in participants aged 60 years and older than in those who were younger than 60 years (8.1  2.7 cm/sec vs. 6.7  1.4 cm/sec, p < 0.001). Similarly, the velocity in the right atrium was increased in the older (9.6  2.8 cm/sec) compared to the younger age group (8.0  2.1 cm/sec, p < 0.01). In this study, both older age and faster heart rates were associated with increased peak atrial contraction velocity (54). Strain/Strain Rate Compared to measurements of tissue Doppler velocities, strain and strain rate measurements provide a purer assessment of contraction and relaxation because they tend to adjust for the components of the velocity vector due to translation and rotation of the heart, and they are less affected by tethering to adjacent myocardial segments. Strain rate is calculated as: (VA  VB)/L, where VA and VB are the velocity of point A and B in the myocardium, and L is the myocardial distance between points A and B (55). To avoid the noise inherent in any differentiation method, strain rate data may be integrated throughout systole to obtain strain, a dimensionless measure of the total deformation that the myocardium undergoes during contraction. Strain is calculated as (L  L0)/L0, where L0 is the original (diastolic) length of the myocardium, and L is the length at end systole. When recorded by tissue Doppler from the apex, normal myocardium demonstrates negative strain during systole and positive strain during diastole. Using tissue Doppler techniques, Sun et al. studied strain and strain rate, in addition to myocardial velocity, in 100 healthy volunteers (56). Measurements were obtained from basal, mid, and apical segments of the visualized left ventricle from the apical fourchamber and two-chamber views. Figure 19 shows the relationship of mean tissue Doppler velocity and strain rate parameters during systole and early and late diastole to age (56). Of note, all measured parameters showed a strong dependence on wall segment position (i.e., basal vs. mid vs. apical). Age dependence was less prominent for peak systolic tissue velocity and strain rate than it was for early and late diastolic tissue velocities and strain rates. Early diastolic velocity and strain rate decreased with age, whereas late diastolic velocity and strain rate increased with age (range of p, 0.01 to

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Figure 19 Age dependence of mean Doppler tissue velocity and SR parameters. To obtain mean Doppler tissue velocity and SR parameters, individual segmental data were averaged over each individual. Age dependence was less prominent for peak systolic tissue velocity (S0 ) and SR (Panels A and B) than for early (E0 ) and late (A0 ) diastolic tissue velocities and SR (Panels C to F). Furthermore, regression coefficients were lower for SR compared with velocity data. Abbreviation: SR, strain rate. Source: From Ref. 56.

0.0001). Although myocardial velocities and strain rate showed a significant association with age, peak systolic strain measures appeared to be less age related. Hees et al. (57) used magnetic resonance imaging and pulsed echo Doppler assessments of myocardial tissue velocities to determine whether the reduction in early diastolic filling in older adults is more closely related to reduced early diastolic left atrial pressure (loading) or to slower LV pressure decline. The authors found (Fig. 20) that older age was associated with a reduced ratio of early diastolic transmitral velocity to LV inflow velocity (Vp) ( p ¼ 0.008), a reduced ratio of early diastolic transmitral velocity— to early diastolic myocardial tissue velocity (E/Em) ( p < 0.0001), increased pulmonary venous systolic fraction ( p < 0.001), and increased pulmonary venous deceleration time ( p ¼ 0.0026) (57). These findings all suggest reduced early diastolic left atrial pressure. Therefore, the authors concluded that reduced early LV filling in older adults may be more closely related to reduced early diastolic left atrial pressure than to slower LV pressure decline. These findings would also help explain the prolonged early diastolic LV relaxation time seen with increasing age.

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Figure 20 Four indexes sensitive to changes in left atrial pressure, PV systolic fraction (top left), deceleration time (bottom left), E/Em (top right) and E/Vp (bottom right), all vary with age ( p < 0.0001, p ¼ 0.0026, p ¼ 0.0001, and p ¼ 0.008, respectively). Abbreviation: PV, pulmonary vein. Source: From Ref. 57.

EPIDEMIOLOGICAL STUDIES IN THE ELDERLY On the basis of M-mode echocardiography, the Framingham study showed that (1) LV hypertrophy is a powerful, independent predictor for mortality and morbidity from CHD, and (2) increased left atrial dimension is associated with an increased risk of stroke (58–60). The Cardiovascular Health Study (CHS) is a multiyear prospective epidemiological study of 5201 men and women older than 65 years recruited from four U.S. field centers: Davis, California; Hagerstown, Maryland; Winston-Salem, North Carolina; and Pittsburgh, Pennsylvania (61). Echocardiography was performed to determine whether echocardiographic measurements, or changes in these measurements, are (1) correlated with traditional risk factors for CHD and stroke, and (2) independent predictors of morbidity and mortality from CHD and stroke. Echocardiographic measurements obtained in CHS included those related to global and segmental LV systolic and diastolic structure and function and left atrial and aortic root dimension (62). For each subject, a baseline two-dimensional (2-D), M-mode (2-D directed), and Doppler ECG was recorded using a standard protocol. Images were digitized and measurements were made using customized computer algorithms. M-mode measurements were made according to American Society of Echocardiography conventions (63), and LV mass was calculated from the formula reported by Devereux et al. LV mass ðgÞ ¼ 0:80  1:04½ðVSTd þ LVIDd þ PWTd Þ3  ðLVIDd Þ3 þ 0:6; 

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where VSTd is ventricular septal thickness at end diastole, LVIDd is LV internal dimension at end diastole, and PWTd is LV posterior wall thickness at end diastole (64). Quality control measures included standardized training of echocardiography technicians and readers, technician observation by a trained echocardiographer, periodic blind duplicate readings with reader review sessions, phantom studies, and quality control audits (62). LV MASS M-mode measurements (2-D directed) of LV mass could not be made in 34% of CHS participants, and this was highly related to age (29% in the 65- to 69-year age group vs. 50% in the 85 or older age group; p < 0.001), white race, male gender, and history of hypertension, diabetes, or CHD. LV mass was found to be significantly higher in men than women, even after multivariate adjustments, and increased modestly with aging (65,66). LV mass increased less than 1 g/yr in both men and women. Of interest, across all CHS age subgroups, the difference in weight-adjusted LV mass by sex was greater in magnitude than the difference related to clinical CHD (Fig. 21). This fact may relate to the relatively high prevalence of subclinical markers of CHD in elderly individuals without clinical disease. After adjustment for traditional CVD risk factors, baseline LV mass was related to six- to seven-year incidence of CHD, congestive heart failure (CHF), and stroke among CHS participants initially free of prevalent disease (67). The highest quartile of LV mass conferred a hazard ratio of 3.36 for incident CHF compared with the lowest quartile. Further, eccentric and concentric LV hypertrophy conferred increased hazard ratios compared with normal LV geometry for both incident CHF (2.95 and 3.32, respectively) and CHD (2.05 and 1.61, respectively). In comparison, in a four-year follow-up of the original Framingham cohort (mean age 69 years), even higher relative risks (7.8 in men and 3.4 in women) for CHD events were found in the highest versus the lowest quartile of risk factor-adjusted LV mass (59).

Figure 21 Bar graph showing weight-adjusted mean LV mass displayed by sex and disease status across 5-year age intervals. Data are computed using the lower age end point and the mean weight for each age category (65 to 69, 70 to 74, 75 to 79, 80 to 84, 85þ years). Weight-adjusted LV mass was significantly associated with sex, disease status, and age. Within each age group, the magnitude of the sex effect exceeded that of the disease effect (e.g., clinical CHD). Abbreviations: LV, left ventricular; CHD, coronary heart disease; HTN, hypertensive.

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LV WALL MOTION In CHS, 4.3% of participants with hypertension but no clinical heart disease and 1.9% of participants with neither clinical heart disease nor hypertension had LV segmental wall motion abnormalities, suggesting silent CHD (66). Multivariate analysis revealed male sex and presence of clinical CHD (both p < 0.001) to be independent predictors of LV akinesis or dyskinesis.

SUBCLINICAL DISEASE Assessments for subclinical CVD at the baseline CHS examination included measures of the ankle–brachial blood pressure index, carotid artery wall thickness and stenosis, ECG and echocardiographic abnormalities, and the Rose Angina and Claudication Questionnaire (Table 4) (68). Participants were followed for an average of 2.4 years (maximum 3 years). For participants without evidence of clinical CVD at baseline, the presence of subclinical disease compared with no subclinical disease was associated with a significantly increased risk of incident CHD in both men and women, including CHD death, nonfatal myocardial infarction, and angina pectoris. For individuals with subclinical disease, the relative risk for incident CHD was 2.0 for men and 2.5 for women, while the relative risk for total mortality was 2.9 for men and 1.7 for women. These increased risks were relatively unchanged after adjustment for other risk factors, including lipoprotein levels, blood pressure, smoking, and diabetes. Consequently, the measurement of subclinical disease provides an approach for identifying high-risk older individuals who may be candidates for more active intervention to prevent clinical disease.

Table 4 Criteria for Clinical and Subclinical Disease in the Cardiovascular Health Study Clinical disease criteria

Subclinical disease criteria

Atrial fibrillation or pacemaker History of intermittent claudication or peripheral vascular surgery

Ankle-arm index <0.9 mmHg Internal carotid wall thickness >80th percentile

History of congestive heart failure History of stroke, transient ischemic attack, or carotid surgery History of coronary artery bypass graft surgery or percutaneous transluminal coronary angioplasty History of angina or use of nitroglycerin History of myocardial infarction a

Common carotid wall thickness >80th percentile Carotid stenosis >25% Major ECG abnormalitiesa Abnormal ejection fraction on echocardiogram Abnormal wall motion on echocardiogram Rose questionnaire claudication positive Rose questionnaire angina positive

According to Minnesota Code, ventricular conduction defects (7–1, 7–2, 7–4); major Q/QS wave abnormalities (1–1, 1–2); left ventricular hypertrophy (high-amplitude R waves with major or minor ST–T abnormalities) (3–1, 3–3, and 4–1 to 4–3 or 5–1 to 5–3); isolated major ST/T wave abnormalities (4–1, 4–2, 5–1, 5–2). Source: From Ref. 37.

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‘‘HEALTHY’’ SUBGROUP An apparently “healthy” subgroup of CHS participants was defined by excluding subjects with clinical heart disease, hypertension, reduced LV ejection fraction, or echocardiographic wall motion abnormalities. The healthy subgroup consisted of 516 men and 773 women, with 339 and 569, respectively, having available echo measurements of LV mass. Preliminary analysis indicated that after adjustment for weight, no adjustment for height was necessary. Likewise, after adjustment for weight, age had only a modest effect on LV mass. Therefore, for simplicity, the reference equations were not expressed as a function of age. There was no evidence of an interaction between sex and weight. Since race was not an independent predictor of LV mass in the original CHS cohort, the reference equations are not race specific. The expected LV mass (g) derived from the CHS healthy subgroup can be calculated from the following equations: Men : 16:6½weight ðkgÞ0:51 Women : 13:9½weight ðkgÞ0:51 If the ratio of observed to expected LV mass is between 0.69 and 1.47, the patient’s LV mass should be considered within the expected range for his or her weight. On the basis of these equations, 28% of the men and 18% of the women with clinical CHD were found to be outside the range of expected LV mass measurements. Exclusions of obese (n ¼ 220) participants from the healthy group had a negligible effect on the reference equations. LV DIASTOLIC FILLING Pulsed Doppler transmitral flow velocities were analyzed as part of the baseline examination in the CHS (62). Early diastolic LV Doppler (transmitral) peak filling velocity decreased, and peak late diastolic (atrial) velocity increased with age in multivariate analyses (all p < 0.001) (69). Early and late diastolic peak filling velocities were both significantly higher in women than in men, even after adjustment for BSA (or height and weight). In multivariate models in the entire cohort and in a healthy subgroup (n ¼ 703), gender, age, heart rate, and blood pressure were most strongly related to early and late diastolic transmitral peak velocities. Higher systolic blood pressure and lower diastolic blood pressure were associated with increased early and late diastolic peak velocities (p < 0.001). These increased early and late diastolic transmitral peak velocities may reflect increased central aortic stiffness. Doppler transmitral velocities were compared among health status subgroups. In multiple regression models adjusted for other covariates, and in analysis-of-variance models examining differences across subgroups adjusted only for age, the subgroup with CHF had the highest early diastolic peak velocities (69). All clinical disease subgroups had higher late diastolic peak velocities than did the healthy subgroup, with the CHF and hypertensive subgroups having the highest age-adjusted means. The hypertensive subgroup had the lowest ratio of early to late diastolic peak velocity, and men with CHF had the highest ratio. Borderline and definite isolated systolic hypertensions were positively associated with LV mass (p < 0.001), as well as with increases in transmitral late peak flow velocity and decreases in the ratio of early to late diastolic peak flow velocity (70). These findings are consistent with previous reports that hypertensive subjects exhibit an abnormal relaxation pattern, whereas CHF patients develop a pattern suggestive of an increased early diastolic LA–LV pressure gradient.

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In summary, echocardiographic imaging and Doppler flow recordings have provided compelling evidence of structural and functional cardiac changes related to aging. In turn, these changes provide important insights into the cardiovascular epidemiology of aging (e.g., mechanisms underlying the increasing prevalence of diastolic HF and atrial fibrillation with advancing age). In addition, these techniques provide a framework for the clinical evaluation of elderly patients with suspected CVD. ACKNOWLEDGMENT The authors acknowledge the expert assistance of Susan Berlin in the preparation of this manuscript. REFERENCES 1. Feigenbaum H. Echocardiography. 5th ed. Philadelphia: Lea & Febiger, 1994:1–133. 2. Talano JV, Gardin JM. Textbook of Two-Dimensional Echocardiography. New York: Grune & Stratton, 1983:1–64, 325–355. 3. Gardin JM, Henry WL, Savage DD, et al. Echocardiographic measurements in normal subjects: evaluation of an adult population without clinically apparent heart disease. J Clin Ultrasound 1979: 7, 439–447. 4. Pombo JE, Troy BL, Russell RD Jr. Left ventricular volumes and ejection fraction by echocardiography. Circulation 1971; 4:480–490. 5. Henry WL, Gardin JM, Ware JH. Echocardiographic measurements in normal subjects from infancy to old age. Circulation 1980; 62:1054–1061. 6. Gardin JM, Savage DD, Ware JH, et al. Effect of age, sex and body surface area on echocardiographic left ventricular wall mass in normal subjects. Hypertension 1987; 9: 1136–1139. 7. Roberts WC, Perloff JK. Mitral valve disease. A clinicopathologic survey of the conditions causing the mitral valve to function abnormally. Ann Intern Med 1972; 77:939–975. 8. Krovetz J. Age-related changes in size of the aortic valve annulus in man. Am Heart J 1975; 90:569–574. 9. Demir M, Acarturk E. Clinical characteristics influence aortic root dimension and blood flow velocity in healthy subjects. Angiology 2001; 5:457–461. 10. Derman U. Changes of the mitral echocardiogram with aging and the influence of atherosclerotic risk factors. Atherosclerosis 1972; 1:349. 11. Borer JS, Bacharach SL, Green MV, et al. Evaluation of clinical utility of real-time computerbased radionuclide cineangiography. Proceedings of the IEEE Computer Society, Rotterdam, 1977. 12. Strandell T. Heart rate, arterial lactate concentration, and oxygen uptake during exercise in old men compared with young men. Acta Physiol Scand 1964; 60:197–213. 13. Brandfonbrener M, Landowne M, Shock NW. Changes in cardiac output with age. Circulation 1955; 12:557–566. 14. Granath A, Strandell T. Relationships between cardiac output, stroke volume and intracardiac pressures at rest and during exercise in supine position and some anthropometric data in healthy old men. Acta Med Scand 1964; 176:447–466. 15. Gerstenblith G. Frederikson J, Yin FCP, et al. Echocardiographic assessment of a normal adult aging population. Circulation 1977; 56:273–278. 16. Snub C, Klein AL, Zachariah PK, et al. Determination of left ventricular mass by echocardiography in a normal population: effect of age and sex in addition to body size. Mayo Clin Proc 1994; 69:205–211.

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17. Savage DD, Levy D, Dannenberg AL, et al. Association of echocardiographic left ventricular mass with body size, blood pressure, and physical activity (The Framingham Study). Am J Cardiol 1990; 65:371–376. 18. Dannenberg AL, Levy D, Garrison RJ. Impact of age on echocardiographic left ventricular mass in a healthy population (The Framingham Study). Am J Cardiol 1989; 64:1066–1068. 19. Gardin JM, Iseri LT, Elkayam U, et al. Evaluation of dilated cardiomyopathy by pulsed Doppler echocardiography. Am Heart J 1983; 106:1057–1065. 20. Elkayam U, Gardin JM, Berkley R, et al. The use of Doppler flow velocity measurements to assess the hemodynamic response to vasodilators in patients with heart failure. Circulation 1983; 67:377–383. 21. Gardin JM, Davidson DM, Rohan MK, et al. Relationship between age, body size, gender, and blood pressure and Doppler flow measurements in the aorta and pulmonary artery. Am Heart J 1987; 113:101–109. 22. Gardin JM, Burns CS, Childs WJ, et al. Evaluation of blood flow velocity in the ascending aorta and main pulmonary artery of normal subjects by Doppler echocardiography. Am Heart J 1984; 107:310–319. 23. Rodeheffer RJ, Gersenblith G, Becker LC, et al. Exercise cardiac output is maintained with advancing age in healthy human subjects: cardiac dilation and increased stroke volume compensate for a diminished heart rate. Circulation 1984; 69:203–213. 24. Lazarus M, Dang TY, Gardin JM, et al. Evaluation of age, gender, heart rate, and blood pressure changes and exercise conditioning on Doppler measured aortic blood flow acceleration and velocity during upright treadmill testing. Am J Cardiol 1988; 62:439–443. 25. Rushmer RF. Initial ventricular impulse: a potential key to cardiac evaluation. Circulation 1964; 29:268–283. 26. Noble M, Tenchard D, Guz A. Left ventricular ejection in conscious dog. I. Measurement and significance of the maximum acceleration of blood from the left ventricle. Circ Res 1966; 19:139–147. 27. Jewitt D, Gabe I, Millis C, et al. Aortic velocity and acceleration measurements in the assessment of coronary heart disease. Eur J Cardiol 1974; 1:299–305. 28. Miyatake K, Okamoto M, Kinishita N, et al. Augmentation of atrial contribution to left ventricular inflow in aging as assessed by intracardiac Doppler flowmetry. Am J Cardiol 1984; 53:586–589. 29. Gardin JM, Rohan MK, Davidson DM, et al. Doppler transmitral flow velocity parameters: relationship between age, body surface area, blood pressure, and gender in normal subjects. Am J Noninvasive Cardiol 1987; 1:3–10. 30. Dabestani A, Johnston WD, Tobis JM, et al. Relation between Doppler transmitral diastolic flow and left ventricular filling [abstr]. J Am Coll Cardiol 1984; 3:612. 31. Rokey R, Kuo LK, Zoghbi WA, et al. Determination of parameters of left ventricular diastolic filling with pulsed Doppler echocardiography: comparison with cineangiography. Circulation 1985; 71:543–550. 32. Mantero A, Gentile F, Azzollini M, et al. Effect of sample volume location on Doppler-derived transmitral inflow velocity values in 288 normal subjects 20 to 80 years old: an echocardiographic, two dimensional color Doppler cooperative study. J Am Soc Echocardiogr 1998; 11:280–288. 33. Gardin JM, Rohan MK, Davidson D, et al. Doppler transmitral flow velocity parameters: relationship between age, body surface area, blood pressure, and gender in normal subjects. Am J Noninvasive Cardiol 1987; 1:3–10. 34. Appleton CP, Hatle LK. The natural history of LV filling abnormalities: assessment by twodimensional and Doppler echocardiography. Echocardiography 1992; 9:437–457. 35. Gentile F, Mantero A, Lippolis A, et al. Pulmonary venous flow velocity patterns in 143 normal subjects aged 20 to 80 years old. An echo 2D colour Doppler cooperative study. Eur Heart J 1997; 18:148–164. 36. Klein AL, Burstow DJ, Tajik AJ, et al. Effects of age on left ventricular dimensions and filling dynamics in 117 normal persons. Mayo Clin Proc 1994; 69:212–224.

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37. Rossvoll O, Hatle LK. Pulmonary venous flow velocities recorded by transthoracic Doppler ultrasound: relation to left ventricular diastolic pressures. J Am Coll Cardiol 1993; 21: 1687–1696. 38. Klein AL, Abdalla I, Murray RD, et al. Age independence of the difference in duration of pulmonary venous atrial reversal flow and transmitral A-wave flow in normal subjects. J Am Soc Echocardiogr 1998; 11:458–465. 39. Derumeauz G, Ovize M, Loufoua J, et al. Assessment of nonuniformity of transmural myocardial velocities by color-coded tissue Doppler imaging: Characterization of normal, ischemic, and stunned myocardium. Circulation 2000; 101(12):1390–1395. 40. Perez-David E, Garcia-Fernandez MA, Ledesma MJ, et al. Age- related intramyocardial patterns in healthy subjects evaluated with Doppler tissue imaging. Eur J. Echocardiography 2005; 6:175–185. 41. Sabbah HN, Marzilli M, Stein PD. The relative role of subendocardium and subepicardium in left ventricular mechanics. Am J Physiol 1981; 240(6):H920–H926. 42. Palka P, Lange A, Fleming AD, et al. Age-related transmural peak mean velocities and peak velocity gradients by Doppler myocardial imaging in normal subjects. Eur Heart J 1996; 17 (6):940–950. 43. Rijcken J, Bovendeerd PH, Schoofs AJ, et al. Optimization of cardiac fiber orientation for homogeneous fiber strain during ejection. Ann Biomed Eng 1999; 27(3):289–297. 44. Arts T, Reneman RS, Venstra PC. A model of the mechanics of the left ventricle. Ann Biomed Eng 1979; 7(3–4):299–318. 45. Sabbah Hn, Marzilli M, Stein PD. The relative role of subendocardium and subepicardium in left ventricular mechanics. Am J Physiol 1981; 240(6):H920–H926. 46. Schwartz A, Sordahl LA, Entman ML, et al. Abnormal biochemistry in myocardial failure. Am J Cardiol 1973; 32(4):407–422. 47. Weisfeldt ML, Loeven WA, Shock NW. Resting and active mechanical proprieties of trabecuale cameae from aged male rates. Am J Physiol 1971; 200(6):1921–1927. 48. Harrison TR, Dixon K, Russell RO, et al. The relation of age to the duration of contraction, ejection, and relaxation of the normal human heart. Am Heart J 1964; 67:189–199. 49. Anversa P, Hiler B, Ricci R, et al. Myocyte cell loss and myocyte hypertrophy in the aging rat heart. J Am Coll Cardiol 1986; 8(6):1441–1448. 50. Henein M, Lidqvist P, Francis D, et al. Tissue Doppler analysis of age-dependency in diastolic ventricular behavior and filling: A cross-sectional study of the healthy hearts (the Umea General Population Heart Study). Eur Heart J 2002; 23(2):162–171. 51. Yamada H, Oki T, Mishiro Y, et al. Effect of aging on diastolic left ventricular myocardial velocities measured by pulsed tissue Doppler imaging in healthy subjects. J Am Soc Echocardiogr 1999; 12:574–581. 52. Onose Y, Takashi O, Mishiro Y, et al. Influence of aging on systolic left ventricular wall motion velocities along the long and short axes in clinically normal patients determined by pulsed tissue Doppler imaging. J Am Soc Echocardiogr 1999; 12:921–926. 53. Nikitin NP, Witte KKA, Ingle L, et al. Longitudinal myocardial dysfunction in healthy older subjects as a manifestation of cardiac ageing. Age and Ageing 2005; 34:343–349. 54. Zhang Q, Kum LLC, Lee PW, et al. Effect of age and heart rate on atrial mechanical function assessed by Doppler tissue imaging in healthy individuals. J Am Soc Echocardiogr 2006; 19:422–428. 55. Heimdal A, Stoylen A, Torp H, et al. Real-time strain rate imaging of the left ventricle by ultrasound. J Am Soc Echocardiogr 1998; 11:1013–1019. 56. Sun JP, Popovic ZB, Greenberg NL, et al. Noninvasive quantification of regional myocardial function using Doppler-derived velocity, displacement, strain rate, and strain in healthy volunteers: Effects of aging. J Am Soc Echocardiogr 2004; 17:132–138. 57. Hees PS, Fleg JL, Dong SJ, et al. MRI and echocardiographic assessment of the diastolic dysfunction of normal aging: altered LV pressure decline or load? Am J Physiol (Heart Circ Physiol) 2004; 286:H782–H788.

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58. Levy D, Garrison RJ, Savage DD, et al. Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N. Engl J Med 1990; 32:1561–1566. 59. Levy D, Garrison RJ, Savage DD, et al. Left ventricular mass and incidence of coronary heart disease in an elderly cohort: The Framingham Heart Study. Ann Intern Med 1989; 110: 101–107. 60. Benjamin E, Levy D, Plehn J, et al. Left atrial size: an independent risk factor for stroke [abstr]. Circulation 1989; 80(suppl 2):615. 61. Fried L, Borhani N, Enright P, et al., for the CHS Collaborative Research Group. Cardiovascular Health Study: design and rational. Ann Epidemiol 1991; 1:263–276. 62. Gardin JM, Wong ND, Bommer W, et al. Echocardiographic design of a multicenter investigation of free-living elderly subjects: the Cardiovascular Health Study. J Am Soc Echocardiogr 1992; 5:63–72. 63. Sahn DJ, DeMaria A, Kisslo J, et al. Committee on M-mode Standardization of the American Society of Echocardiography. Recommendations regarding quantitation in M-mode echocardiography: results of a survey of echocardiographic methods. Circulation 1978; 58: 1072–1083. 64. Devereux RB, Alonso DR, Lutas EM, et al. Echocardiographic assessment of left ventricular hypertrophy: comparison with necropsy findings. Am J Cardiol 1986; 57:450–458. 65. Gardin JM, Siscovick D, Anton-Culver H, et al. Age and gender relations of left ventricular mass and wall motion in elderly subjects with no clinical heart disease: the Cardiovascular Health Study (CHS) [abstr]. Circulation 1992; 84(4):I–672. 66. Gardin JM, Siscovick D, Anton-Culver H, et al. Sex, age and disease affect echocardiographic left ventricular mass and systolic function in the free-living elderly: the Cardiovascular Health Study. Circulation 1995; 91:1739–1748. 67. Gardin JM, McClelland R, Kitzman D, et al. M-mode echocardiographic predictors of six- to seven-year incidence of coronary heart disease, stroke, congestive heart failure, and mortality in an elderly cohort (the Cardiovascular Health Study). Am J Cardiol 2001; 87:1051–1057. 68. Kuller LH, Shemanski L, Psaty BM, et al. Subclinical disease as an independent risk factor of cardiovascular disease. Circulation 1995; 92:720–726. 69. Gardin JM, Arnold AM, Bild DE, et al. Left ventricular diastolic filling in the elderly: the Cardiovascular Health Study. Am J Cardiol 1998; 82(3):345–351. 70. Psaty BM, Furbert CD, Kuller LH, et al. Isolated systolic hypertension and subclinical cardiovascular disease in the elderly. Initial findings from the Cardiovascular Health Study. JAMA 1992; 268:1287–1291. 71. Drayer J, Gardin JM, Weber MA, et al. Changes in cardiac anatomy and function during therapy with alpha-methyldopa: an echocardiographic study. Curr Ther Res 1982; 32:856–865.

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Morphological Features of the Elderly Heart William Clifford Roberts Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, Texas, U.S.A.

INTRODUCTION As in any body tissue or organ, changes take place in the cardiovascular system as life progresses. Some of these changes allow easy identification of the very elderly heart when examining autopsy cardiac specimens as unknowns. The “normal” elderly heart has relatively small ventricular cavities and relatively large atria and great arteries. The ascending aorta and left atrium, in comparison with the relatively small left ventricular cavity, appear particularly large. The coronary arteries increase in both length and width; the former, particularly in association with the decreasing size of the cardiac ventricles, results in arterial tortuosity. (The young river is straight and the old one winding.) The leaflets of each of the four cardiac valves thicken with age, particularly the atrioventricular valves; these have a smaller area to occupy in the ventricles because of the diminished size of the latter. Histological examination discloses large quantities of lipofuscin pigment in myocardial cells; some contain mucoid deposits (mucoid degeneration). These changes appear to affect all population groups of elderly individuals regardless of where they reside on the earth or their level of serum lipids. An elevated systemic arterial pressure appears to both accelerate and amplify these normal expected cardiac changes of aging. Both the aorta and its branches and the major pulmonary arteries and their branches enlarge with age. Because the enlargement is in both the longitudinal and the transverse dimension, the aorta, like the coronary arteries, tends to become tortuous. This process is further amplified as the vertebral bodies become smaller and the height becomes somewhat shorter. The major pulmonary arteries appear to be too short and have too low a pressure to dilate longitudinally. The amount of information at necropsy in very elderly persons is relatively sparse. In 1983, Waller and Roberts (1) described some clinical and necropsy findings in 40 American patients aged 90 years and older. In 1988, Lie and Hammond (2) reported findings at necropsy in 237 patients aged 90 years and older. In 1991, Gertz and associates (3) described composition of coronary atherosclerotic plaques in 18 persons aged 90 years and older. In 1993, Roberts (4) described cardiac necropsy findings in an additional

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53 patients aged 90 years and older. In 1995, Shirani et al. (5) described cardiac findings at necropsy in 366 Americans aged 80 to 89 years, and in 1998, Roberts (6) described cardiac findings at necropsy in six centenarians. Also, in 1998, Roberts and Shirani (7) compared cardiovascular findings in 490 patients studied at necropsy in the three age categories: 80–89; 90–99, and;
100 years. This chapter expands on that previous comparative study. METHODS Patients The files of the Pathology branch, National Heart, Lung, and Blood Institutes, National Institutes of Health, Bethesda, Maryland, from 1959 to 1993, and those of the Baylor University Medical Center, Dallas, Texas, beginning January 1993, were searched for all accessioned cases of patients aged 80 years and older. Of 511 such cases found, adequate clinical information was available in 490 necropsy patients, and they are the subject of this chapter. The clinical and cardiac morphological records, photographs, and postmortem radiographs, histological slides, and the initial gross description of the heart were reviewed. All 490 hearts were originally examined by WCR, who recorded gross morphological abnormalities in each case. Sources of Patients Of the 490 cases, the hearts in 412 were obtained from 12 Washington, D.C., area hospitals, and the hearts in the other 78 cases, from hospitals outside that area, including 25 from Baylor University Medical Center. Of the 490 hearts, 37 (8%) were examined in 1970 or before, 153 (31%) from 1971 through 1980, 244 (50%) from 1981 through 1990, and 56 (11%) from 1991 through 1997. Definitions Sudden coronary death was defined as death within six hours from the onset of new symptoms of myocardial ischemia in the presence of morphological evidence of significant atherosclerotic coronary artery disease (
1 major epicardial coronary artery narrowed >75% in cross-sectional area by atherosclerotic plaque). Most patients who died suddenly did so outside a hospital; a few, however, died shortly after admission to an emergency room. Sudden, out-of-hospital death also occurred in some patients with cardiac disease other than atherosclerotic coronary artery disease. In each case, an underlying cardiac disease generally accepted to cause sudden death was present at necropsy. Acute myocardial infarction was defined as a grossly visible left ventricular wall lesion confirmed histologically to represent coagulation-type myocardial necrosis. Ischemic cardiomyopathy was defined as chronic congestive heart failure associated with a transmural healed myocardial infarct and a dilated left ventricular cavity. Cardiac Morphological Data Hearts were fixed in 10% phosphate-buffered formalin for 3 to 15 days before examination. They were “cleaned” of parietal pericardium and postmortem intracavity clot, and the pulmonary trunk and ascending aorta were incised approximately 2 cm

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cephalad to the sinotubular junction. Heart weight was then measured on accurate scales by WCR (Lipsaw scale before 1971, accurate to 10 g, and Mettler P1210 scale after 1971, accurate to 0.1 g). Heart weight was considered increased if it was
350 g in women and >400 g in men. Most hearts were studied by cutting the ventricles transversely at approximately 1-cm-thick intervals from apex to base parallel to the atrioventricular groove posteriorly. In each heart, the sizes of cardiac ventricular cavities (determined by gross inspection), presence of left ventricular necrosis (acute myocardial infarct) and fibrosis (healed myocardial infarct), status of the four cardiac valves, and the maximal degree of cross-sectional luminal narrowing in each of the three major (left anterior descending, left circumflex, and right) epicardial coronary arteries were recorded. RESULTS Number of Patients in Each of the Three Groups Certain clinical and necropsy cardiac findings in the 490 cases are summarized in Table 1 and illustrated in Figures 1 through 19. The 490 patients were divided into three groups: the octogenarians (80–89 years) [n ¼ 391 (80%)], the nonagenarians (90–99 years) Table 1 Certain Clinical and Necropsy Findings in 490 Patients Aged 80–103 Years Age group (yr) Variables 1. 2. 3. 4. 5. 6. 7. 8. 9.

10.

11.

80–89 (n ¼ 391)

Mean age (yr) 84  4 Male:female 194 (50%):97 (50%) Angina pectoris 137 (35%) Acute myocardial 78 (20%) infarction Chronic congestive 140 (36%) heart failure Systemic 174 (44%) hypertension (history) Diabetes mellitus 56 (14%) Atrial fibrillation 57 (15%) Heart weight (g): 185–900 (449) range (mean) Men 230–830 (493) Women 185–900 (409) Cardiomegaly Men > 400 g 103/154 (67%) Women > 350 g 133/165 (81%) Cardiac calcific deposits None 43 (11%) Present 348 (89%) Coronary arteries 304 (78%) Aortic valve cusps 164 (42%) Heavy (stenosis) 43 (11%) Mitral annulus 146 (37%) Heavy 52 (13%) Papillary muscle 37 (9%)

90–99 (n ¼ 93)


100 (n ¼ 6)

93  4 52 (56%):41 (44%) 5 (5%) 18 (18%)

102 2/4 0 0

23 (25%)

0

50 (54%)

0

8 (9%) 35 (38%) 220–660 (420)

0 0 240–410 (328)

285–660 (436) 220–630 (406)

335 and 410 (372) 240–385 (306)

27/49 (55%) 23/42 (55%)

1/2 1/4

3 90 89 59 8 42 11 42

(3%) (97%) (96%) (63%) (9%) (45%) (12%) (45%)

0 6 (100%) 5 5 0 2 0 6

(Continued)

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Table 1 Certain Clinical and Necropsy Findings in 490 Patients Aged 80–103 Years (Continued) Age group (yr) Variables

80–89 (n ¼ 391)

90–99 (n ¼ 93)


100 (n ¼ 6)

12. Number of patients with 0, 1, 2, or 3 major (right, left anterior descending, left circumflex) coronary arteries ; >75% in cross-sectional area 0 159 (41%) 33 (35%) 2 1 67 (59%) 20 (65%) 2 2 71 232 (59%) 32 60 (65%) 24 3 94 (59%) 8 (65%) 0 Mean 1.7 1.5 1.5 13. Number of major coronary arteries (3/patient) ; >75% in cross-sectional area by plaque 0 0/477 0/99 0/6 1 67/201 20/60 2/6 2 142/213 64/96 4/6 3 282/282 24/24 0 Total 491/1173 (42%) 108/279 (39%) 6/18 (33%) 14. Left ventricular necrosis and/or fibrosis Necrosis only 54/(14%) 10 (11%) 0 Fibrosis only 101 (26%) 20 (21%) 2 Both 37 (9%) 5 (5%) 0 15. Ventricular cavity dilatation Neither 222 (57%) 58 (62%) 4 One 84 (21%) 4 (4%) 2 Right ventricle 42 2 2 Left ventricle 42 2 2 Both 85 (22%) 31 (34%) 0 16. Cardiac amyloidosis 14 (4%) 8 (9%) 0 (massive)

[n ¼ 93 (19%)], and the centenarians (
100 years) [n ¼ 6 (l%)]. Of the 490 cases, 248 (51%) were women and 242 (49%) were men.

CLINICAL FINDINGS The clinical manifestations of the various cardiac disorders probably represent minimal numbers: many patients, apparently, were unable to provide much clinical information, many came to the hospital from nursing homes, and many had varying degrees of dementia. Nevertheless, angina pectoris was noted in the records of 137 (35%) of the 391 octogenarians, in 5 (5%) of the 93 nonagenarians, and in none of the centenarians. A history of hospitalization for an illness compatible with acute myocardial infarction was present in 78 (20%) of the 391 octogenarians, in 18 (19 %) of the 93 nonagenarians, and in none of the six octogenarians. Chronic congestive heart failure was present in 36% (140/391) of the octogenarians, in 25% (23/93) of the nonagenarians, and in none of the six centenarians. A history of systemic hypertension was present in 45% (174/391) of the octogenarians, in 54% (50/93) of the nonagenarians, and in none of the centenarians.

Morphological Features of the Elderly Heart

Figure 1 Tortuous and heavily calcified coronary arteries in a 95-year-old woman (SH #A80–74) who never had symptoms of cardiac dysfunction and who died from a perforated gastric ulcer. (Top left): Postmortem radiogram of the excised R, LM, LAD, and LC coronary arteries. (Top center): Radiogram of a portion of the heart after removing the walls of the atria and most of the walls of the ventricles. (Top right and lower panels): Photomicrographs of coronary arteries at sites of maximal narrowing by calcified atherosclerotic plaques. (Movat stains; magnification: 17, reduced 40%). This case illustrates extensive calcific deposits in the coronary arteries without significant luminal narrowing. Abbreviations: R, right; LM, left main; LAD, left anterior descending; LC, left circumflex; MVA, mitral valve annulus.

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Figure 2 Coronary arteries in a 95-year-old man (SH #A79–77) who never had symptoms of cardiac dysfunction and who died from cancer. (Top): Aorta and coronary arteries from above. (Bottom): Radiograms of Ao and excised coronary arteries that contain calcific deposits. Abbreviations: Ao, aortic root; FD, first diagonal; LAD, left anterior descending; LC, left circumflex; LM, left main; R, right.

Diabetes mellitus was present in 14% (56/391) of the octogenarians, in 9% (8/93) of the nonagenarians, and in none of the centenarians. CAUSES OF DEATH The causes of death in the 490 patients are summarized in Table 2. A cardiac condition was the cause of death in 51% (198/391) of the octogenarians, in 30% (30/99) of the nonagenarians, and in none of the centenarians. A noncardiac but vascular condition was

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Table 2 Causes of Death in the 490 Necropsy Patients Aged 80–103 Years

I. Cardiac A. Coronary artery disease 1. Acute myocardial infarction 2. Chronic congestive heart failure 3. Sudden 4. Coronary bypass B. Valvular heart disease 1. Aortic stenosis 2. Aortic regurgitation 3. Mitral regurgitation 4. Mitral stenosis C. Primary cardiomyopathy 1. Hypertrophic 2. Idiopathic dilated D. Secondary cardiomyopathy 1. Amyloidosis 2. Hemosiderosis 3. Myocarditis E. Pericardial heart disease II. Vascular, noncardiac A. Stroke B. Abdominal aortic aneurysm C. Peripheral arterial disease D. Aortic dissection E. Pulmonary embolism III. Noncardiac, nonvascular A. Cancer B. Infection C. Fall complication D. Other

Age group (yr) 80–89 (n ¼ 391)

90–99 (n ¼ 93)


100 (n ¼ 6)

198 (51%) 129/198 (65%) 90 15 19 7 41/198 (21%) 33 2 5 1 7/198 (4%) 4 3 16/198 (8%) 14 1 1 3/198 (2%) 52 (13%) 17/52 (33%) 14/52 (33%) 11/52 (21%) 4/52 (8%) 6*/52 (11%) 141 (36%) 52/141 (37%) 37/141 (26%) 10/141 (7%) 42/141 (30%)

30 (32%) 12/30 (40%) 12 3 3 0 3/30 (10%) 3 0 0 0 1/30 (3%) 0 1 8/30 (27%) 8‘ 0 0 0 19 (20%) 6/19 (32%) 5/19 (26%) 5/19 (26%) 0/19 (0) 3/19* (16%) 44 (47%) 13/44 (29%) 17/44 (39%) 3/44 (7%) 11/44 (25%)

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 6 (100%) 0/6 0/6 3/6 3/6

All had underlying chronic obstructive pulmonary disease.

responsible for death in 13% (52/391) of the octogenarians and in 20% (19/93) of the nonagenarians. A noncardiac and nonvascular condition was responsible for death in 36% (141/391) of the octogenarians, in 47% (44/93) of the nonagenarians, and in all of the centenarians. CARDIAC NECROPSY FINDINGS Cardiac findings at necropsy are tabulated in Table 1. Heart Weight The mean heart weights were largest in the octogenarians and smallest in the centenarians (449 g vs. 420 g vs. 328 g). Heart weight was increased (>400 g in men; >350 g in women) in 131 (64%) of the 205 men and in 157 (74%) of the women, and the percentage was highest in the octogenarians.

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Figure 3 Heart and coronary arteries in a 93-year-old woman who was hospitalized with worsening chronic congestive heart failure. (Top left): Postmortem radiogram showing calcific deposits in the R, LAD, and LC coronary arteries and in the MVA and aortic valve. (Top right): View of RV and LV and VS showing a transmural scar (arrows). (Bottom): Coronary arteries at sites of maximal narrowing. (Movat stains; magnification: 17, reduced 40%). Abbreviations: R, right; LAD, left anterior descending; LC, left circumflex; MVA, mitral valve annulus; RV, right ventricle; LV, left ventricle; VS, ventricular septum; LM, left main.

Figure 4 This 91-year-old woman (LRC #3) had a “typical” clinical acute myocardial infarct, which was fatal. (Left): Postmortem radiogram showing calcific deposits in the R, LM, LAD, and LC coronary arteries. (Right): View of the left and right (RV) ventricles showing transmural necrosis and fibrosis (arrows) and dilated ventricles. Abbreviations: R, right; LM, left main; LAD, left anterior descending; LC, left circumflex; VS, ventricular septum.

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Figure 5 This 90-year-old woman (SH #A82–1) had no symptoms of cardiac dysfunction and died from a ruptured fusiform abdominal aortic aneurysm. (Left): Postmortem radiogram of the entire heart showing calcific deposits in the LAD, LC, and LM coronary arteries. (Right): View of heart cut in an anteroposterior fashion (M-mode or long-axis two-dimensional echocardiographic view) showing a dilated LA and LV. Abbreviations: LAD, left anterior descending; LC, left circumflex; LM, left main; LA, left atrium; A and P, anterior and posterior mitral valve leaflets; Ao, aorta; RV, right ventricle; VS, ventricular septum.

Calcific Deposits in the Heart Calcific deposits were present in the heart at necropsy in 444 (91%) of the 490 patients and were most common in the coronary arteries in 81% (398/490)—in all cases being located in atherosclerotic plaques and not in the media; in the aortic valve cusps in 47% (228/490)—heavy enough to result in aortic stenosis in 10% (51/490); mitral valve annulus in 39% (190/490)—very heavy deposits in 13% (63/490), and in the apices of one or both left ventricular papillary muscles in 17% (85/490). The cardiac calcific deposits were more frequent and heavier in the nonagenarians than in the octogenarians.

Numbers of Patients with Narrowing of One or More Major Epicardial Coronary Arteries Among the 490 patients, 194 (40%) had none of the three major (right, left anterior descending, and left circumflex) epicardial coronary arteries narrowed by plaque >75% in crosssectional area; 89 (18%) had one artery so narrowed; 105 (21%) had two arteries so narrowed; and 94 (19%) had all three arteries so narrowed. The percentage of patients in each of the three groups with no arteries and one, two, and three arteries narrowed >75% was similar.

Figure 6 This 97-year-old man (GT # 69A–585) had complete heart block and had a pacemaker inserted when he was 91-years old. (Left): Radiogram of heart at necropsy showing calcific deposits in the LAD, LC, and R coronary arteries and a pacemaker wire in the RV. (Right): Electrocardiogram. Abbreviations: LAD, left anterior descending; LC, left circumflex; R, right; RV, right ventricle; LV, left ventricle.

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Figure 7 This 96-year-old woman (DCGH #68A80) had chronic congestive heart failure from dilated cardiomyopathy. Her total serum cholesterol level was 108 mg/dL. (Left): Postmortem radiogram of the R, LM, LAD, LC, FD, and left OM coronary arteries showing no calcific deposits. (Right): Right coronary artery section devoid of calcium or narrowing. (Movat stain; magnification: 16, reduced 23%.). Abbreviations: R, right; LM, left main; LAD, left anterior descending; LC, left circumflex; FD, first diagonal; OM, obtuse marginal.

Number of Major Coronary Arteries (Three/Patient) Narrowed in Cross-Sectional Area by Plaque

>75%

Among the 490 patients, a total of 1470 major epicardial coronary arteries were examined: 865 (59%) arteries had insignificant (<75% in cross-sectional area) narrowing and 605 (41%) had narrowing by plaque >75% in cross-sectional area. The percentage of arteries significantly narrowed was similar in each of the three groups (42% vs. 39% vs. 33%). Acute and Healed Myocardial Infarcts Grossly visible foci of left ventricular wall (includes ventricular septum) necrosis (acute infarcts) without associated left ventricular scars (healed infarcts) were found in 64 (13%) patients, foci of left ventricular fibrosis without associated necrosis were observed in 123 patients (25%), and foci of both necrosis and fibrosis were found in 42 patients (9%). Thus, a total of 229 (47%) of the 490 patients had grossly visible evidence of acute or healed myocardial infarcts or both. The percentages of patients with myocardial lesions of ischemia were similar among the octogenarians and nonagenarians. Ventricular Cavity Dilatation One or both ventricular cavities were dilated (by gross inspection) in 218 (44%) of the 490 patients and no significant differences were observed in the three groups.

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Figure 8 R, LM, LAD, and LC coronary arteries at sites of maximal narrowing in a 103-year-old woman (GT #70A301). She never had evidence of cardiac dysfunction and died from complications of a duodenal ulcer. The coronary arteries are devoid of calcium and of significant narrowing. (Elastic-van Gieson’s stain; magnification 16, reduced 31%.). Abbreviations: R, right; LM, left main; LAD, left anterior descending; LC, left circumflex.

Cardiac Amyloidosis Grossly visible amyloid (confirmed histologically) in ventricular and atrial myocardium as well as in atrial mural endocardium was present in 22 patients (4%). In these 22 patients, the amyloidosis was symptomatic and fatal. A number of other patients who had no gross evidence of cardiac amyloidosis had small foci in the heart on histological study. These minute deposits did not cause symptoms of cardiac dysfunction. In the 22 patients with fatal cardiac amyloidosis, deposits of amyloid also were present in several other body organs at necropsy. ELECTROCARDIOGRAPHIC FINDINGS Information on electrocardiograms was available on 30 of the 99 patients aged 90 years and older. Of the 30 patients, three had electrocardiograms recorded during acute myocardial infarction. The electrocardiograms in all three, however, disclosed only atrial fibrillation and complete left bundle branch block, and these findings in these patients

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Figure 9 Mean percentage cross-sectional area narrowing by atherosclerotic plaques in 1789 segments (5 mm) of the four major epicardial coronary arteries in 36 necropsy patients aged 90 years and older, 10 of whom had angina pectoris or acute myocardial infarction, or both, and 26 of whom did not. The mean percentage of narrowing for each 5-mm segment differs significantly in the group with clinical evidence of myocardial ischemia (55%) and the group without such evidence.

were known to be present before the fatal acute myocardial infarction. The electrocardiograms in the other 27 patients were not recorded during periods of acute myocardial infarction. Of the 30 patients on whom electrocardiographic information was available, 8 had clinical evidence of heart disease and 22 did not; the findings are summarized in Table 2. The total 12-lead QRS voltage ranged from 82 to 251 mm (mean 151; 10 mm ¼ 1 mV). In the 19 women, the total voltage ranged from 82 to 251 mm (mean 158) and, in the 5 men, from 105 to 154 mm (mean 101; p < 0.05). The total 12-lead QRS voltage did not correlate with either heart or body weight. The 24 patients in whom the total 12-lead QRS voltage was measured were separated into two groups: 8 patients in whom clinical evidence of cardiac dysfunction was present (coronary heart disease in five, massive cardiac amyloid in two, and aortic valve stenosis in one) and 16 patients without such evidence. Comparison of the total QRS voltage in the 8 patients with and in the 16 patients without clinical evidence of heart disease disclosed no significant difference (mean 147 mm vs. 152 mm). Breakdown on the eight patients with cardiac dysfunction did show some differences: the total 12-lead QRS voltage in the five patients with angina pectoris or acute myocardial infarction ranged from 123 to 163 mm (mean 143); in the two patients with massive cardiac amyloidosis it was 102 and 117 mm (mean 109), and in the one patient with aortic valve stenosis it was 238 mm. Of the 29 patients on whom

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Figure 10 Mean percentage cross-sectional area (XSA) narrowing by atherosclerotic plaques in the 5-mm segments of the right, left main, left anterior descending, and left circumflex coronary arteries in the 36 patients in whom the four major coronary arteries in their entirety were available for examination. The 36 patients were classified into 10 with and 26 without clinical evidence of myocardial ischemia. For each of the four categories of narrowing, a highly significant difference in the amount of narrowing was observed.

information was available, 18 (62%) received digitalis and only two appeared to have evidence of digitalis toxicity.

COMMENTS This study describes findings in a large group (n ¼ 490) of patients aged 80 years and older studied at necropsy, and it compares certain clinical and necropsy findings in the octogenarians, nonagenarians, and centenarians. Despite study of nearly 500 patients, only 6 (1%) lived 100 years or longer, and only 93 (19%) lived into the tenth decade of life. Nevertheless, the ratio of one centenarian for every 65 octogenarians is much higher than expected. In general, it takes 10,000 persons to reach age 85 before one reaches age 100 (8). Another finding was the high frequency of men: 248 men (51%) and 242 women (49%). A higher than expected percentage of men may have resulted in part from receiving a number of these cases from a Veterans Administration Hospital and from a retirement home filled almost entirely by men.

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Figure 11 A 92-year-old woman (GT #78A58) with clinically recognized and eventually fatal aortic valve stenosis. (Top left): Stenotic aortic valve from above. (Top right): Postmortem radiogram showing heavy calcific deposits in the AV and in the MVA region. (Bottom left): Radiogram of the heart at necropsy showing calcific deposits in the coronary arteries, in the aortic valve, and in the mitral annular region. (Bottom right): Long-axis view of heart (M-mode or two-dimensional long-axis view) showing a small LV cavity, a thickened and “sigmoid-shaped” VS, and the stenotic aortic valve just above the RV outflow tract. Abbreviations: AV, aortic valve; MVA, mitral valve annular; LV, left ventricular; VS, ventricular septum RV, right ventricular; PV, pulmonic valve; R, right; LM, left main; LAD, left anterior descending coronary arteries; LA, left atrium.

The causes of death were divided into three major types: cardiac ¼ 228/490 (47%), vascular but noncardiac ¼ 71/490 (14%), and noncardiac and nonvascular ¼ 191/490 (39%). The frequency of a cardiac condition causing death decreased with increasing age groups (51% vs. 32% vs. 0), and the frequency of a noncardiac and nonvascular condition causing death increased with increasing age groups (36% vs. 47% vs. 100%). Among the cardiac conditions, coronary artery disease was the problem in 62% (141/228) of the patients, and the other cardiac conditions, mainly aortic valve stenosis [36/228(16%)] and cardiac amyloidosis [22/228(10%)], in the other 38%. Stroke, rupture of an abdominal aortic aneurysm, and complications of peripheral arterial atherosclerosis were the major

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Figure 12 (A) A 90-year-old woman (GT #80A126) with heavy mitral valve annular calcific deposits that reduced the mitral valve orifice to <1 cm in diameter. The unusual feature of the mitral calcium in this patient was that it was not only located behind the posterior mitral leaflet (mitral annular region) but it also extended across the anterior mitral leaflet, nearly producing a letter O), as has been described previously. She died from rupture of a descending thoracic aortic aneurysm. (B) View of the left ventricle at the level of the tips of the mitral leaflets, showing a very small cavity. Abbreviation: VS, ventricular septum.

vascular (noncardiac) conditions causing death. Of the noncardiac and nonvascular causes of death, cancer and infection, mainly pneumonia, were the major conditions, 35% (65/185) and 29% (54/185), respectively, among the octogenarians and nonagenarians. The cardiac necropsy findings focused primarily on calcific deposits in the coronary arteries, aortic valve cusps, and mitral valve annulus and their consequences, and, to a lesser extent, on heavy amyloid deposits in the heart. Calcific deposits were present in the atherosclerotic plaques of one or more epicardial coronary arteries in 81% (398/490) of the patients, on the aortic aspects of the aortic valve cusps in 47% (228/490), in the mitral annular regional in 39% (190/490), and in one or both left ventricular papillary in 25% (122/490). The calcific deposits tended to be less frequent in the octogenarians. The frequent presence of calcific deposits in the coronary arteries, aortic valve cusps, and mitral annular region in the same patient suggests that the cause of the calcific deposits in each of these three locations is the same. The calcific deposits in the coronary arteries indicate the presence of atherosclerosis because calcium occurs in the coronary arteries, with one exception (9), only in the plaques and not in the media. It is reasonable to believe that the calcific deposits in and on the aortic cusps, at least when this valve is threecuspid, are another manifestation of atherosclerosis. Because mitral annular calcium in this older population is nearly always associated with calcium in the coronary arteries, it is also reasonable to believe that mitral annular calcium in persons aged 80 years and older also is a manifestation of atherosclerosis. Calcium in a papillary muscle appears to be a consequence of aging and not a direct manifestation of atherosclerosis. When the deposits of calcium on the aortic aspects of the aortic valve cusps are extensive, the cusps may become relatively or absolutely immobile, resulting in aortic

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Figure 13 A 97-year-old woman (SH #A81–62) who never had clinical evidence of cardiac dysfunction and who died from cancer. (A) External view of anterior surface of the heart showing and increased amount of subepicardial fat. (B) Postmortem radiogram showing calcific deposits in the MVA and AV. (C) Radiogram of the excised coronary arteries showing a few calcific deposits. (D) View of AV and PV from above. (E) View of left ventricle showing clacific deposits (arrows) in the papillary muscles. (F) Calcific deposits in the mitral annular region (arrows). Abbreviations: Ao, aorta; LV, left ventricle; PT, pulmonary trunk; RV, right ventricle; LA, left atrium; RA, right atrium; LAD, left anterior descending; LC, left circumflex; LM, left main; R, right; MVA, mitral valve annulus; AV, aortic valve; PV, pulmonic valve.

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Figure 14 M-mode echocardiogram obtained 10 months before death (SH #80–18). The Ao has a larger diameter than the LA. The LV cavity is small. Calcium is present in the mitral annular region. Abbreviations: Ao, ascending aorta; LA, left atrium; LV, left ventricular. Source: Dr. Robert Montgomery, Bethesda, Maryland, U.S.A.

valve stenosis. These valves usually lack commissural fusion (i.e., adherence of two cusps together near the lateral attachments) and, therefore, aortic regurgitation is usually absent. Although it is most often associated with some degree of mitral regurgitation, mitral annular calcium may result in mitral stenosis, provided the mitral annular calcium is “massive” and the left ventricular cavity is small and the wall quite thickened (10). Although the calcific deposits in the epicardial coronary arteries were located entirely in atherosclerotic plaques, which are located in the intima, the presence of calcific deposits in the coronary arteries in this older population did not necessarily indicate the presence of significant (>75% cross-sectional area) luminal narrowing. In contrast, the presence of calcific deposits in epicardial coronary arteries in persons aged less than 65 years generally indicates the presence of significant luminal narrowing. The calcific deposits tended to occur in each of the four major (right, left main, left anterior descending, and left circumflex) epicardial arteries and were always larger in the proximal than in the distal halves of the right, left anterior descending, and left circumflex arteries or, if small, limited to their proximal halves. The plaques consisted mainly (87%  8%) of fibrous tissue with calcific deposits forming 7%  6% of the plaques (3). The percentage of patients with narrowing >75% in cross-sectional area by plaque of one or more major epicardial coronary arteries was similar in all the three age groups, as was the percentage of major coronary arteries narrowed significantly. In 36 patients (all
90 years of age), each of the four major coronary arteries were divided into 5-mm-long segments and the degree of cross-sectional area narrowing by atherosclerotic plaque was determined for each segment. Of the 1789 5-mm segments in the 36 patients, the average amount of cross-sectional area narrowing by atherosclerotic plaques per segment was 42% (range, 19–69). Of the 467 5-mm segments in the 10 patients with clinical evidence of coronary artery disease, the average amount of crosssectional area narrowing per segment was 55% (range, 43–69), and of the 1322 5-mm segments in the 26 patients without clinical evidence of coronary artery disease, it was 38% (range, 19–40; p < 0.01). Among 129 patients aged 22 to 85 years (mean 56), the amount of cross-sectional area narrowing by atherosclerotic plaques per segment averaged 67%; in the control subjects, that is, those without symptomatic coronary artery

Figure 15 A 95-year-old man (SH #79–77) who never had symptoms of cardiac dysfunction and died from sarcoma. The coronary arteries are shown in Figure 2. (Left): Radiogram of heart at necropsy showing considerable enlargement of the aorta in comparison to the ventricles. (Right): Aortic valve from above. The coronary arteries were excised before the radiogram and photographs were taken. Abbreviations: LV, left ventricle; RV, right ventricle; R, right; L, left; P, posterior sinuses of Valsalva.

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Figure 16 A 90-year-old man (DCGH #69A391) with chronic, eventually fatal, congestive heart failure from clinically unrecognized cardiac amyloidosis. (A) External view of the heart showing prominent LV and LAA. (B) Right-to-left longitudinal cut of the heart (four-chamber, twodimensional echocardiographic view) showing thickened ventricular walls and dilated RA and LA. (C) Photomicrograph of a portion of the left ventricle showing extensive amyloid deposits. (D) Photomicrograph of LA wall showing amyloid deposits in endocardium (E) and in myocardium (M). (Hematoxylin and eosin; magnification: 100 (C) and 25 (D), both reduced by 35%). Abbreviations: LV, left ventricle; LAA, left atrial appendage; RA, right atrium; LA, left atrium; PT, pulmonary trunk; RAA, right atrial appendage; RV, right ventricle; VS, ventricular septum.

disease, cross-sectional area narrowing averaged 32%. The mean percentage of 5-mm coronary segments narrowed by 76–100% in cross-sectional area in the 36 patients was 13% (range, 2–89); of the 10 patients with symptomatic coronary artery disease, the mean was 19% (range, 10–34); and of the 26 patients without symptomatic coronary artery disease, the mean was 7% (range, 2–28) (p < 0.05). The mean of 19% in patients with symptomatic coronary artery disease aged 90 years and older was half of that observed in patients younger than 85 years (mean 56) with fatal coronary artery disease, and the mean of 7% was nearly three times that observed in the younger patients without fatal coronary artery disease (11).

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Figure 17 Electrocardiograms in four patients, each recorded at age 90 years or older. None ever had symptoms of cardiac dysfunction, and each died from noncardiac conditions. (Top left): The electrocardiogram was recorded 43 days before death (A66–13) and showed a normal heart (weight 270 g). (Top right): The electrocardiogram was recorded 11 days before death (GT #68A325) and showed left QRS axis deviation and a slightly prolonged PR interval (heart weight 400 g). (Bottom left): This electrocardiogram was recorded 28 days before death (A64–62) and showed left axis deviation and complete left bundle branch block (heart weight 320 g). (Bottom right): This electrocardiogram was recorded 128 days before death (SH #A80–74) and showed atrial fibrillation, left axis deviation, and complete right bundle branch block (heart weight 440 g).

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Figure 18 Various QRS complexes, and how each was measured. Source: From Siegel RJ, Roberts WC. Electrocardiograph observations in severe aortic valve stenosis: correlative necropsy study of clinical, hemodynamic, and ECG variables demonstrating relation of 12-lead QRS amplitude to peak systolic transaortic pressure gradient. Am Heart J 1982; 103:210–221.

These detailed morphological studies of the coronary arteries in these very elderly persons suggest that the degree of severe coronary narrowing necessary to have a fatal or nearly fatal coronary event is considerably less than that necessary to have a coronary event in younger patients. Moreover, these studies indicate that these very elderly patients without symptoms of coronary artery disease have distinctly more coronary luminal narrowing by atherosclerotic plaque than control subjects who are younger (mean age, 52 years) (11). The latter observation suggests that coronary artery disease may be underdiagnosed clinically in the very elderly. Clinical diagnosis of cardiac and other conditions in patients aged 80 years and over, particularly those aged 90 years and older, appears more difficult than in younger persons. Historical information may be difficult to obtain because of impaired intellect on the part of the patient and an impaired diagnostic pursuit on the part of the physician. Physicians caring for these very elderly persons may focus primarily on the prevention of suffering and only secondarily on accurate diagnosis or longer-term therapy. Patients aged 90 years and over generally have outlived their spouses and private physicians and are often “inherited” by nursing home physicians, who may have limited access to earlier medical records. Angina pectoris appears particularly difficult to diagnose in the very elderly because they may not be able to describe this symptom. Acute myocardial infarction is

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Figure 19 Cardiac changes in the very elderly. The LA cavity enlarges, and the LV cavity becomes smaller. The amount of space available for the mitral leaflets decreases with aging, and consequently the number of scallops in the leaflets appears to increase. Abbreviations: LA, left atrium; LV, left ventricle. Source: From Roberts WC, Perloff JK. Mitral valvular disease. A clinicopathologic survey of the conditions causing the mitral valve to function abnormally. Ann Intern Med 1972; 77:939–975.

also difficult to diagnose clinically, but it is often fatal in the very elderly. Furthermore, the electrocardiogram is not as useful in diagnosis of acute myocardial infarction in the very elderly because left bundle branch block is frequent and, of course, it prevents the appearance of typical changes. Serial recordings of electrocardiograms also appear to be quite infrequent in the very elderly. Physical examination in the very elderly may be both difficult and misleading. The lack of mobility may prevent proper positioning of the elderly patient for proper examining. Precordial murmurs, although common, infrequently indicate significant functional abnormality. Although calcific deposits in the aortic valve are common, actual aortic valve stenosis is not nearly as frequent. Likewise, although mitral annular calcific deposits are common, these calcific deposits rarely narrow the mitral orifice or produce significant mitral regurgitation. Electrocardiographic abnormalities are common in elderly persons. Of my patients for whom electrocardiograms were available, all had one or more abnormalities recorded, the most frequent being abnormal axis, atrial fibrillation, and complete bundle branch block. Although 15 of the 30 patients had cardiomegaly (>350 g in women; >400 g in men) at necropsy, only one had voltage criteria for left ventricular hypertrophy. Likewise, only one had low voltage. Measurement of the QRS amplitude in each of the 12 leads was performed in 24 patients. The total QRS voltage was similar in the eight patients with and

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in the 16 patients without clinical evidence of cardiac disease (mean 147 vs. 152 mm; 10 mm ¼ 1 mV). SUMMARY Certain clinical and necropsy cardiac findings are described and compared in 391 octogenarians (80%), 93 nonagenarians (19%), and 6 centenarians (1%). The numbers of men and women were similar [248(51%)] and [242(49%)]. The cause of death was cardiac in 228 patients (47%), vascular but noncardiac in 71 (14%), and noncardiac and nonvascular in 191 (39%). The frequency of a cardiac condition causing death decreased with increasing age groups (51% vs. 32% vs. 0), and the frequency of a noncardiac, nonvascular condition causing death increased with increasing age groups (36% vs. 47% vs. 100%). Among the cardiac conditions causing death, coronary artery disease was the problem in 61% (141/228) followed by aortic valve stenosis in 16% (36/228) and cardiac amyloidosis in 10% (22/228). Calcific deposits were found at necropsy in the coronary arteries in 81% (398/490) of the patients, in the aortic valve in 47% (228/490), in the mitral annular area in 39% (190/490), and in one or both left ventricular papillary muscles in 25% (122/490). The calcific deposits tended to be less frequent in the octogenarians. Three hundred (61%) of the 490 patients had one or more major coronary arteries narrowed by more than 75% in cross-sectional area by plaque, and the percentage of patients in each of the three age groups was similar to the percentage of coronary arteries significantly narrowed in them. REFERENCES 1. Waller BF, Roberts WC. Cardiovascular disease in the very elderly. Analysis of 40 necropsy patients aged 90 years or over. Am J Cardiol 1983; 51:403–421. 2. Lie JT, Hammond PI. Pathology of the senescent heart: anatomic observations on 237 autopsy studies of patients 90 to 105 years old. Mayo Clin Proc 1988; 63:552–564. 3. Gertz SD, Malekzadeh S, Dollar AL, et al. Composition of atherosclerotic plaques in the four major epicardial coronary arteries in patients
90 years of age. Am J Cardiol 1991; 67: 1228–1233. 4. Roberts WC. Ninety-three hearts
90 years of age. Am J Cardiol 1993; 71:599–602. 5. Shirani J, Yousefi J, Roberts WC. Major cardiac findings at necropsy in 366 American octogenarians. Am J Cardiol 1995; 75:151–156. 6. Roberts WC. The heart at necropsy in centenarians. Am J Cardiol 1998; 81:1224–1225. 7. Roberts WC, Shirani J. Comparison of cardiac findings at necropsy in octogenarians, nonagenarians, and centenarians. Am J Cardiol 1998; 82:627–631. 8. Fries JF. Aging, natural death, and the compression of morbidity. N Engl J Med 1980; 303:130–135. 9. Lachman AS, Spray TL, Kerwin DM, et al. Medial calcinosis of Monc-keberg. A review of the problem and a description of a patient with involvement of peripheral, visceral, and coronary arteries. Am J Cardiol 1977; 63:615–622. 10. Hammer WJ, Roberts WC, deLeon AC Jr. “Mitral stenosis” secondary to combined “massive” mitral annular calcific deposits and small, hypertrophied left ventricles. Am J Med 1978; 64:371–376. 11. Roberts WC. Qualitative and quantitative comparison of amounts of narrowing by atherosclerotic plaques in the major epicardial coronary arteries at necropsy in sudden coronary death, transmural acute myocardial infarction, transmural healed myocardial infarction, and unstable angina pectoris. Am J Cardiol 1989; 4:324–328.

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Cardiovascular Drug Therapy in the Elderly William H. Frishman Department of Medicine, New York Medical College/Westchester Medical Center, Valhalla, New York, U.S.A.

Wilbert S. Aronow Divisions of Cardiology, Geriatrics, and Pulmonary/Critical Care, Department of Medicine, New York Medical College, Valhalla, New York, U.S.A.

Angela Cheng-Lai Department of Pharmacy, Montefiore Medical Center, Bronx, New York, U.S.A.

Cardiovascular disease is the greatest cause of morbidity and mortality in the elderly, and cardiovascular drugs are the most widely prescribed drugs in this population. Since many cardiovascular drugs have narrow therapeutic windows in the elderly, the incidence of adverse effects from using these drugs is also highest in the elderly. The appropriate use of cardiovascular drugs in the elderly requires knowledge of age-related physiologic changes, the effects of concomitant diseases that alter the pharmacokinetic and pharmacodynamic effects of cardiovascular drugs, and drug interactions. PHARMACOKINETIC CONSIDERATIONS IN THE ELDERLY Absorption Age-related physiologic changes, which may affect absorption, include reduced gastric secretion of acid, decreased gastric emptying rate, reduced splanchnic blood flow, and decreased mucosal absorptive surface area (Table 1). Despite these physiologic changes, the oral absorption of cardiovascular drugs is not significantly affected by aging, probably because most drugs are absorbed passively (1). Bioavailability There are almost no data available for age-related changes in drug bioavailability for routes of administration other than the oral route (2). The bioavailability of cardiovascular drugs depends on the extent of drug absorption and on first-pass metabolism by the liver and/or the 99

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Table 1 Physiologic Changes with Aging Potentially Affecting Cardiovascular Drugs Process

Physiologic change

Result

Absorption

Reduced gastric acid production

Reduced tablet dissolution and decreased solubility of basic drugs Decreased absorption for acidic drugs Less opportunity for drug absorption

Distribution

Metabolism

Excretion

Reduced gastric emptying rate Reduced GI mobility, GI blood flow, absorptive surface Decreased total body mass. Increased proportion of body fat Decreased proportion of body water Decreased plasma albumin, disease-related Increased a1-acid glycoprotein, altered relative tissue perfusion Reduced liver mass, liver blood flow, and hepatic metabolic capacity

Drugs affected

Increased Vd of highly lipid-soluble drugs

; b blockers, central a agonists

Decreased Vd of hydrophilic drugs Changed % of free drug, Vd, and measured levels of bound drugs

: digoxin & ACE inhibitors : disopyramide and warfarin, lidocaine, propranolol

Accumulation of metabolized drugs

: propranolol, nitrates, lidocaine, diltiazem, warfarin, labetalol, verapamil, mexiletine digoxin, ACE inhibitors, antiarrhythmic drugs, atenolol, sotalol, nadolol

Reduced glomerular Accumulation of renally filtration, renal tubular cleared drugs function, and renal blood flow

Abbreviations: GI, gastrointestinal; ACE, angiotensin-converting enzyme. Source: From Ref. 181.

wall of the gastrointestinal (GI) tract. In the elderly, the absolute bioavailability of drugs such as propranolol, verapamil, and labetalol is increased because of reduced first-pass hepatic extraction (3). However, the absolute bioavailability of prazosin in the elderly is reduced (4). Drug Distribution With aging there is a reduction in lean body mass (5) and in total body water (6), causing a decrease in volume of distribution (Vd) of hydrophilic drugs. This decrease leads to higher plasma concentrations of hydrophilic drugs such as digoxin and angiotensin converting enzyme (ACE) inhibitors with the first dose in the elderly (7). The increased proportion of body fat that occurs with aging also causes an increased Vd for lipophilic drugs. This leads to lower initial plasma concentrations for lipophilic drugs such as most b blockers, antihypertensive drugs, and central a agonists. The level of a1-acid glycoprotein increases in the elderly (8). Weak bases, such as disopyramide, lidocaine, and propranolol, bind to a1-acid glycoprotein. This may cause a reduction in the free fraction of these drugs in the circulation, a decreased Vd, and a higher initial plasma concentration (9). In the elderly, there is also a tendency for plasma albumin concentration to be reduced. (10). Weak acids, such as salicylates and warfarin, bind extensively to albumin. Decreased binding of drugs such as warfarin to plasma albumin may result in increased free-drug concentrations, resulting in more intense drug effects (11).

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Half-Life The half-life of a drug (or of its major metabolite) is the length of time in hours that it takes for the serum concentration of that drug to decrease to half of its peak level. This definition can be described by the kinetic equation: t½ ¼ 0.693  Vd/Cl, where t½ is directly related to drug distribution and inversely to clearance (Cl). Therefore, changes in Vd and/or Cl due to aging, as previously mentioned, can affect the half-life of a drug. In elderly patients, an increased half-life of a drug means a longer time until steady-state conditions are achieved. With a prolonged half-life of a drug, there may be an initial delay in maximum effects of the drug and prolonged adverse effects. Table 2 lists the pharmacokinetic changes, routes of elimination, and dosage adjustment for common cardiovascular drugs used in the elderly. Table 2 Pharmacokinetic Changes, Route of Elimination, and Dosage Adjustment of Selected Cardiovascular Drugs in the Elderly Drug

t½

Vd

Cl

a-Adrenergic agonists (centrally acting) Clonidine – – –

Primary route(s) of elimination Hepatic/renal

Guanabenz

–

–

–

Hepatic

Guanfacine

:

–

;

Hepatic/renal

Methyldopa

–

–

–

Hepatic

a1-selective adrenergic antagonists (peripherally acting) Doxazosin : : :a Hepatic Prazosin

:

–

–

Hepatic

Terazosin

:

–

–

Hepatic

Angiotensin-converting enzyme inhibitors Benazepril : – ; Captopril NS – ;

Renal Renal

Enalapril

–

–

–

Renal

Fosinopril Lisinopril

– :

– NS

– ;

Hepatic/renal Renal

Moexipril

–

–

–

Hepatic/renal

Perindopril

–

–

;

Renal

Quinapril

–

–

–

Renal

Ramipril

–

–

–

Renal

Trandolapril

–

–

–

Hepatic/renal

Dosage adjustment Initiate at lowest to response Initiate at lowest to response Initiate at lowest to response Initiate at lowest to response

dose; titrate dose; titrate dose; titrate dose; titrate

Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response No adjustment needed Initiate at lowest dose; to response Initiate at lowest dose; to response No adjustment needed Initiate at lowest dose; to response Initiate at lowest dose; to response Initiate at lowest dose; to response Initiate at lowest dose; to response Initiate at lowest dose; to response Initiate at lowest dose; to response

titrate titrate

titrate titrate titrate titrate titrate titrate

(Continued )

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Table 2 Pharmacokinetic Changes, Route of Elimination, and Dosage Adjustment of Selected Cardiovascular Drugs in the Elderly (Continued ) Drug

t½

Vd

Angiotensin II receptor blockers Candesartan – – Eprosartan – – Irbesartan NS – Losartan – – Olmesartan – – Telmisartan – – Valsartan : – Antiarrhythmic agents Class I Disopyramide : –

Cl

Primary route(s) of elimination

Dosage adjustment

– ; – – – – –

Hepatic/renal Hepatic/biliary/renal Hepatic Hepatic Renal/biliary Hepatic/biliary Hepatic

No No No No No No No

;

Renal

Initiate at lowest dose; to response Initiate at lowest dose; to response Initiate at lowest dose; to response No adjustment needed No adjustment needed Initiate at lowest dose; to response No adjustment needed Initiate at lowest dose; to response No adjustment needed

Flecainide

:

:

;

Hepatic/renal

Lidocaine

:

:

NS

Hepatic

Mexilitine Moricizine Procainamide

– – –

– – –

– – ;

Hepatic Hepatic Renal

Propafenone Quinidine

– :

– NS

– ;

Hepatic Hepatic

–

;

Hepatic/renal

– –

– –

Hepatic/biliary Renal

Tocainide : Class II (see b blockers) Class III Amiodarone – Bretylium – Dofetilide

–

–

–

Renal

Ibutilide Sotalol

– –

– –

– –

Hepatic Renal

Class IV (see calcium channel blockers) Other antiarrhythmics Adenosine – – – Atropine Antithrombotics Anticoagulants Argatroban Bivalirudin

adjustment adjustment adjustment adjustment adjustment adjustment adjustment

needed needed needed needed needed needed needed

titrate titrate titrate

titrate

titrate

No adjustment needed Initiate at lowest dose; titrate to response Adjust dose based on renal function No adjustment needed Adjust dose based on renal function

Erythrocytes/vascular No adjustment needed endothelial cells Hepatic/renal Use usual dose with caution

–

–

–

– –

– –

– –

Dalteparin Desirudin

– –

– –

– –

Hepatic/biliary Renal/proteolytic cleavage Renal Renal

Enoxaparin

–

–

–

Renal

Fondaparinux

:

–

;

Renal

Use usual dose with caution Adjust dose based on renal function Use usual dose with caution Adjust dose based on renal function Adjust dose based on renal function Use usual dose with caution (Continued )

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Table 2 Pharmacokinetic Changes, Route of Elimination, and Dosage Adjustment of Selected Cardiovascular Drugs in the Elderly (Continued ) Drug

Primary route(s) of elimination

t½

Vd

Cl

Heparin

–

–

–

Lepirudin

:

–

;

Tinzaparin Warfarin

– NS

– NS

– NS

– – NS – – – :

– – – – – – –

– ; – – – ; ;

Unknown Hepatic/renal Hepatic Hepatic/biliary Renal/plasma Hepatic Renal

Use Use Use Use Use Use Use

– – –

– – –

– – –

Use usual dose with caution Use usual dose with caution Use usual dose with caution

– –

– –

Hepatic Hepatic Circulating antibodies/ reticuloendothelial system Hepatic Hepatic

–

–

Renal

Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response

Antiplatelets Abciximab Aspirin Clopidogrel Dipyridamole Eptifibatide Ticlopidine Tirofiban Thrombolytics Alteplase Reteplase Streptokinase

Tenecteplase – Urokinase – b-Adrenergic blockers Nonselective without ISA Nadolol NS

Hepatic/ Use usual dose with caution reticuloendothelial system Renal Adjust dose based on renal function Renal Use usual dose with caution Hepatic Initiate at lowest dose; titrate to response

Propranolol

:

NS

;

Hepatic

Timolol

–

–

–

Hepatic

NS

;

Renal

b1 selective without ISA Atenolol :

Dosage adjustment

usual usual usual usual usual usual usual

dose dose dose dose dose dose dose

with with with with with with with

caution caution caution caution caution caution caution

Use usual dose with caution Use usual dose with caution

Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response Use usual dose with caution Initiate at lowest dose; titrate to response

Betaxolol

–

–

–

Hepatic

Bisoprolol

–

–

–

Hepatic/renal

Esmolol Metoprolol

– NS

– NS

– NS

Erythrocytes Hepatic

b1 selective with ISA Acebutolol

:

;

–

Hepatic/biliary

Initiate at lowest dose; titrate to response

Nonselective with ISA Carteolol

–

–

–

Renal

Initiate at lowest dose; titrate to response (Continued )

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Table 2 Pharmacokinetic Changes, Route of Elimination, and Dosage Adjustment of Selected Cardiovascular Drugs in the Elderly (Continued ) t½

Vd

Cl

Primary route(s) of elimination

Penbutolol

–

–

–

Hepatic

Pindolol

–

–

–

Hepatic/renal

Dual acting Carvedilol

–

–

–

Hepatic/biliary

Labetalol

–

–

NS

Hepatic

Calcium channel blockers Amlodipine :

–

;

Hepatic

Drug

Dosage adjustment Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response Use usual dose with caution Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response No initial adjustment needed Initiate at lowest dose; titrate to response Use usual dose with caution Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response

Bepridil Diltiazem

– :

– NS

– ;

Hepatic Hepatic

Felodipine

–

NS

;

Hepatic

Isradipine

–

–

–

Hepatic

Nicardipine Nifedipine

NS :

– NS

– ;

Hepatic Hepatic

Nimodipine Nisoldipine

– –

– –

– –

Hepatic Hepatic

Verapamil

:

NS

;

Hepatic

–

–

–

Renal/hepatic

Initiate at lowest dose; titrate to response

– – : –

NS – NS –

– – ; –

Renal/hepatic Hepatic Renal Hepatic

No No No No

initial initial initial initial

adjustment adjustment adjustment adjustment

– – – – – – – – – – – –

– – – – – – – – – – – –

– – – – ; – – – – – – –

Renal Unknown Renal Renal Renal Unknown Hepatic Renal Renal Unknown Unknown Unknown

No No No No No No No No No No No No

initial initial initial initial initial initial initial initial initial initial initial initial

adjustment needed adjustment needed adjustment needed adjustment needed adjustment needed adjustment needed adjustment needed adjustment needed adjustment needed adjustment needed adjustment needed adjustment needed (Continued )

Direct renin inhibitors Aliskiren Diuretics Loop Bumetanide Ethacrynic Acid Furosemide Torsemide Thiazides Bendroflumethiazide Benzthiazide Chlorothiazide Chlorthalidone Hydrochlorothiazide Hydroflumethiazide Indapamide Methyclothiazide Metolazone Polythiazide Quinethazone Trichlormethiazide

needed needed needed needed

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Table 2 Pharmacokinetic Changes, Route of Elimination, and Dosage Adjustment of Selected Cardiovascular Drugs in the Elderly (Continued ) Primary route(s) of elimination

Drug

t½

Vd

Cl

Potassium-Sparing Amiloride Spironolactone Triamterene

– – :

– – –

; – –

Renal No initial adjustment needed Hepatic/biliary/renal No initial adjustment needed Hepatic/renal Initiate at lowest dose; titrate to response

–

Hepatic

–

No adjustment needed

–

Hepatic/biliary

–

Use usual dose with caution Cellular internalization and lysosomal proteolysis/ proteolytic cleavage/renal filtration

–

Hepatic/renal

Aldosterone receptor antagonist Eplerenone – – Aquaretic Conivaptan – – Endothelin receptor antagonist Bosentan – – Human B-type natriuretic peptide Nesiritide – –

Inotropic and vasopressor agents Inamrinone – – Digoxin

:

;

;

Dobutamine

–

–

–

Dopamine

–

–

–

Epinephrine

–

–

–

Isoproterenol

–

–

–

Metaraminol

–

–

–

Methoxamine

–

–

–

Midodrine Milrinone Norepinephrine

– – –

– – –

– – –

Phenylephrine

–

–

–

Vasopressin

–

–

–

–

–

–

–

–

–

Lipid-lowering agents BAS Cholestyramine Colestipol

Dosage adjustment

No initial adjustment needed

Use usual dose with caution

Initiate at lowest dose; titrate to response Renal Initiate at lowest dose; titrate to response Hepatic/tissue Initiate at lowest dose; titrate to response Renal/hepatic/plasma Initiate at lowest dose; titrate to response Sympathetic nerve Initiate at lowest dose; titrate endings/plasma to response Renal Initiate at lowest dose; titrate to response Hepatic/biliary/renal Initiate at lowest dose; titrate to response Unknown Initiate at lowest dose; titrate to response Tissue/hepatic/renal No initial adjustment needed Renal Adjust based on renal function Sympathetic nerve Initiate at lowest dose; titrate endings/hepatic to response Hepatic/intestinal Initiate at lowest dose; titrate to response Hepatic Adjust dose based on hepatic function and response

Not absorbed in GI tract Not absorbed in GI tract

No adjustment needed No adjustment needed (Continued )

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Table 2 Pharmacokinetic Changes, Route of Elimination, and Dosage Adjustment of Selected Cardiovascular Drugs in the Elderly (Continued ) Drug

Primary route(s) of elimination

t½

Vd

Cl

–

–

–

Not absorbed in GI tract

No adjustment needed

SCAI Ezetimibe

–

–

–

Small intestine/ hepatic/Biliary

No adjustment needed

FADS Fenofibrate

–

–

–

Renal

Gemfibrozil – – Nicotinic acid – – HMG CoA Reductase Inhibitors Atorvastatin : – Fluvastatin – – Lovastatin – – Pravastatin – – Rosuvastatin – – Simvastatin – –

– –

Hepatic/renal Hepatic/renal

Initiate at lowest dose; titrate to response No adjustment necessary No initial adjustment needed

– – – – – –

Hepatic/biliary Hepatic Hepatic/fecal Hepatic Hepatic/fecal Hepatic/fecal

No initial adjustment needed No initial adjustment needed No initial adjustment needed No initial adjustment needed No initial adjustment needed Initiate at lowest dose; titrate to response

–

Hepatic/renal

Initiate at lowest to response Initiate at lowest to response Initiate at lowest to response Initiate at lowest to response

Colesevelam

Neuronal and Ganglionic Blockers Guanadrel – – Guanethidine

–

–

–

Hepatic/renal

Mecamylamine

–

–

–

Renal

Reserpine

–

–

–

Hepatic/fecal

Vasodilators Alprostadil

–

–

–

Pulmonary/renal

Cilostazol Diazoxide

– –

– –

– –

Hepatic/renal Hepatic/renal

Epoprostenol

–

–

–

Hepatic/renal

Fenoldopam Hydralazine

– –

– –

– –

Hepatic Hepatic

ISDN

–

–

–

Hepatic

ISMN Isoxsuprine

NS –

– –

NS –

Hepatic Renal

Minoxidil

–

–

–

Hepatic

Nitroglycerin

–

–

–

Hepatic

Nitroprusside

–

–

–

Hepatic/renal/ erythrocytes

Dosage adjustment

dose; titrate dose; titrate dose; titrate dose; titrate

Initiate at lowest dose; titrate to response No adjustment necessary Initiate at lowest dose; titrate to response Initiate at usual dose with caution No adjustment necessary Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response No adjustment necessary Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response Initiate at lowest dose; titrate to response Use usual dose with caution (Continued )

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Table 2 Pharmacokinetic Changes, Route of Elimination, and Dosage Adjustment of Selected Cardiovascular Drugs in the Elderly (Continued ) t½

Vd

Cl

Primary route(s) of elimination

Papaverine

–

–

–

Hepatic

Pentoxifylline

–

–

;

Hepatic/renal

Sildenafil

–

–

–

Hepatic/fecal

Drug

Dosage adjustment Initiate at lowest dose; titrate to response Use usual dose with caution; dose reduction may be needed Initiate at lowest dose; titrate to response

a

Increase in Cl is small compared with increase in VD. Abbreviations: t½, half-life; Vd, volume of distribution; Cl, clearance; :, increase; ;, decrease; –, no information or not relevant; NS, no significant change; LMWH, low molecular weight heparin; ISA, intrinsic sympathomimetic activity; GI, gastrointestinal; BAS, bile acid sequestrants; SCAI, selective cholesterol absorption inhibitors; FADS, fibric acid derivatives; HMG CoA, hydroxymethylglutaryl coenzyme A; ISDN, isosorbide dinitrate; ISMN, isosorbide mononitrate. Source: From Ref. 182.

Drug Metabolism Decreased hepatic blood flow, liver mass, liver volume, and hepatic metabolic capacity occur in the elderly (12). There is a reduction in the rate of many drug oxidation reactions (phase 1) and little change in drug conjugation reactions (phase 2). These changes in the elderly may result in higher serum concentrations of cardiovascular drugs that are metabolized in the liver, including propranolol, lidocaine, labetalol, verapamil, diltiazem, nitrates, warfarin, and mexiletine. Drug Excretion With aging there is a reduction in the total number of functioning nephrons and thereby a parallel decline in both glomerular filtration rate and renal plasma flow (13,14). The age-related decline in renal function is likely the single most important physiologic change causing pharmacokinetic alterations in the elderly. The change in renal function with aging is insidious and poorly characterized by serum creatinine determinations, although serum creatinine measurements remain one of the most widely used tests for gauging renal function. To estimate renal function from a serum creatinine value requires its being indexed for muscle mass, which is difficult in even the most skilled hands. Creatinine is a byproduct of creatine metabolism in muscle and its daily production correlates closely with muscle mass. Thus, the greater the muscle mass, the higher the “normal serum creatinine.” For example, in a heavily muscled male, a serum creatinine value of 1.4 mg/dL might be considered normal, though such a value may be considered grossly abnormal in an individual with less muscle, such as an aged individual. A safer way to estimate renal function in the elderly is by use of a urine-free formula, such as the Cockcroft–Gault formula (15): Creatinine clearance ðmL=minÞ ¼ ð140  ageÞ  body weight ðkgÞ= 72  Screat ðmg=dLÞ For females, the results of this equation can be multiplied by 0.85 to account for the small muscle mass in most females. It should be appreciated that creatinine clearance is reciprocally related to serum creatinine concentrations, such that a doubling of serum

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creatinine represents an approximate halving of renal function. The axiom that glomerular filtration rate is reciprocally related to serum creatinine is most important with the first doubling of serum creatinine. For example, a serum creatinine value of 0.6 mg/dL in an elderly subject doubles to 1.2 mg/dL, and with this doubling creatinine clearance falls from 80 cc/min to about 40 cc/min. The National Kidney Foundation guidelines use the Modification of Diet in Renal Disease (MDRD) equation to estimate the glomerular filtration rate (16). The MDRD equation is Glomerular filtration rate ðmL=min=1:73m2 Þ ¼ 186  Screat 1:154  age0:203  0:742 if female  1:210 if Black ð16Þ: The reduced clearance of many drugs primarily excreted by the kidneys causes their half-life to be increased in the elderly. Cardiovascular drugs known to be excreted by the kidney, via various degrees of filtration and tubular secretion, include digoxin, diuretics, ACE inhibitors, antiarrhythmic medications (bretylium, disopyramide, flecainide, procainamide, and tocainide), and the b blockers (atenolol, bisoprolol, carteolol, nadolol, and sotalol). Typically, a renally cleared compound begins to accumulate when creatinine clearance values drop below 60 cc/min. An example of this phenomenon can be seen with ACE inhibitors (17) wherein accumulation begins early in the course of renal functional decline. Moreover, ACE inhibitor accumulation in the elderly is poorly studied in the case of many of the ACE inhibitors, particularly as relates to the “true level of renal function” when an otherwise healthy elderly subject undergoes formal pharmacokinetic testing. Thus, it has not been uncommon for elderly subjects with serum creatinine values as high as 2.0 mg/dL to be allowed entry into a study whose primary purpose is to determine the difference in drug handling of a renally cleared compound in young versus elderly subjects. PHARMACODYNAMICS There are numerous physiologic changes with aging that affect pharmacodynamics with alterations in end-organ responsiveness (Table 3). Increased peripheral vascular resistance is the cause of systolic and diastolic hypertension in the elderly (18). Inappropriate Table 3 Characteristics of the Elderly Relative to Drug Response Physiologic changes

Changes in response

Decreased cardiac reserve Decreased LV compliance due to thickened ventricular wall, increased blood viscosity, decreased aortic compliance, increased total and peripheral resistance Decreased baroreceptor sensitivity Diminished cardiac and vascular responsiveness to b agonists and antagonists Suppressed renin-angiotensin-aldosterone system

Potential for heart failure Decrease of cardiac output

Increased sensitivity to anticoagulant agents Concurrent illnesses Multiple drugs Sinus and AV node dysfunction

Tendency to orthostatic hypotension Decreased sensitivity to b agonists and antagonists Theoretically decreased response to ACE inhibitors, but not observed Increased effects of warfarin Increased drug-disease interactions Increased drug-drug interactions Potential for heart block

Abbreviations: LV, left ventricular; ACE, angiotensin-converting enzyme; AV, atrioventricular. Source: From Ref. 181.

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sodium intake and retention may contribute to increased arteriolar resistance and/or plasma volume. Cardiac output, heart rate, renal blood flow, glomerular filtration rate, and renin levels decline with age. Increased arterial stiffness, resulting from changes in the arterial media and an increase in arterial tonus and arterial impedance, increases systolic blood pressure and contributes to a widened pulse pressure. Maintenance of a-adrenergic vasoconstriction with impaired b-adrenergic-mediated vasodilation may be an additional contributory factor to increased peripheral vascular resistance. The cardiovascular response to catecholamines and carotid arterial baroreflex sensitivity are both decreased in the elderly. Left ventricular (LV) mass and left atrial dimension are increased, and there is a reduction in both the LV early diastolic filling rate and volume (18). The pharmacodynamic, chronotropic, and inotropic effects of b agonists and b blockers on b1-adrenergic receptors are diminished in the elderly (19–21). The density of b receptors in the heart is unchanged in the elderly, but there is a decrease in the ability of b-receptor agonists to stimulate cyclic adenosine monophosphate production (22). There are also agerelated changes in the cardiac conduction system, as well as an increase in arrhythmias in the elderly. In the Framingham Study, the prevalence of atrial fibrillation was 1.8% in persons 60 to 69 years old, 4.8% in those 70 to 79 years old, and 8.8% in those 80 to 89 years old (23). In a study of 3624 elderly patients (mean age 81 years), the prevalence of atrial fibrillation was 16% (1160) in elderly men and 13% (2464) in elderly women (24). In elderly patients with unexplained syncope, a 24-hour ambulatory electrocardiogram (ECG) should be obtained to rule out the presence of second-degree or third-degree atrioventricular block or sinus node dysfunction with pauses of more than 3 seconds not seen on the resting ECG. These phenomena were observed in 21 of 148 patients (14%) with unexplained syncope (25). These 21 patients included 8 with sinus arrest, 7 with advanced second-degree atrioventricular block, and 6 with atrial fibrillation with a slow ventricular rate that is not drug induced. Unrecognized sinus node or atrioventricular node dysfunction may become evident in elderly persons after drugs such as amiodarone, b blockers, digoxin, diltiazem, procainamide, quinidine, or verapamil are administered. Clinical use of these drugs in the elderly, therefore, must be carefully monitored. USE OF CARDIOVASCULAR DRUGS IN THE ELDERLY Digoxin Digoxin has a narrow toxic-therapeutic ratio, especially in the elderly (26). Decreased renal function and lean body mass may increase serum digoxin levels in this population. Serum creatinine may be normal in elderly persons despite a marked reduction in creatinine clearance, thereby decreasing digoxin clearance and increasing serum digoxin levels. Older persons are also more likely to take drugs that interact with digoxin by interfering with bioavailability and/or elimination. Quinidine, cyclosporin, itraconazole, calcium preparations, verapamil, amiodarone, diltiazem, triamterene, spironolactone, tetracycline, erythromycin, propafenone, and propantheline can increase serum digoxin levels. Hypokalemia, hypomagnesemia, hypercalcemia, hypoxia, acidosis, acute and chronic lung disease, hypothyroidism, and myocardial ischemia may also cause digitialis toxicity despite normal serum digoxin levels. Digoxin may also cause visual disturbances (27), depression, and confusional states in older persons, even with therapeutic blood levels. Indications for using digoxin are slowing a rapid ventricular rate in patients with supraventricular tachyarrhythmias such as atrial fibrillation, and treating patients with congestive heart failure (CHF) in sinus rhythm associated with abnormal LV ejection fraction that does not respond to diuretics, ACE inhibitors, and b blockers with a class IIa

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indication (28). Digoxin should not be used to treat patients with CHF in sinus rhythm associated with normal LV ejection fraction. By increasing contractility through increasing intracellular calcium ion concentration, digoxin may increase LV stiffness and increase LV filling pressures, adversely affecting LV diastolic dysfunction. Since almost half the elderly patients with CHF have normal LV ejection fractions (29,30), the LV ejection fraction should be measured in all older patients with CHF so that appropriate therapy may be given (31). Many older patients with compensated CHF who are in sinus rhythm and are on digoxin may have the drug withdrawn without decompensation in cardiac function (32,33). A post hoc subgroup analysis of data from women with an LV ejection fraction less than 45% in the Digitalis Investigator Group (DIG) study showed by multivariate analysis that digoxin significantly increased the risk of death among women by 23% (absolute increase of 4.2%) (34). A post hoc subgroup analysis of data from men with an LV ejection fraction less than 45% in the DIG study showed that digoxin significantly reduced mortality by 6% if the serum digoxin level was 0.5 to 0.8 ng/mL, insignificantly increased mortality by 3% if the serum digoxin level was 0.8 to 1.1 ng/mL, and significantly increased mortality by 12% if the serum digoxin level was greater than 1.2 ng/mL (35). Another post hoc subgroup analysis of data from all 1926 women with systolic or diastolic HF in the DIG study showed that digoxin significantly increased mortality by 20% in women (36). However, digoxin did not increase mortality in women with an LV ejection fraction less than 35% and a serum digoxin level of 0.5 to 1.1 ng/mL (37). In women with an LV ejection fraction less than 35% and a serum digoxin level greater than 1.2 ng/mL, digoxin significantly increased mortality 1.83 times (37). Therapeutic levels of digoxin do not reduce the frequency or duration of episodes of paroxysmal atrial fibrillation detected by 24-hour ambulatory ECGs (38). In addition, therapeutic concentrations of digoxin do not prevent the occurrence of a rapid ventricular rate in patients with paroxysmal atrial fibrillation (38,39). Many elderly patients are able to tolerate atrial fibrillation without the need for digoxin therapy because the ventricular rate is slow as a result of concomitant atrioventricular nodal disease. Some studies have suggested that digoxin may decrease survival after acute myocardial infarction (MI) in patients with LV dysfunction (40,41). Leor et al. (42) showed that digoxin may exert a dose-dependent deleterious effect on survival in patients after acute MI, although other studies have not confirmed this finding (43,44). Eberhardt et al. (45) demonstrated in the Bronx Longitudinal Aging Study that digoxin use in the elderly without evidence of CHF was an independent predictor of mortality. The results of the DIG study trial demonstrated that digoxin could be used in older subjects with CHF, but in lower doses than previously employed in clinical practice (46). Diuretics The Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure recommended thiazide-like diuretics or b blockers as initial drug treatment of hypertension because these drugs had been demonstrated to reduce cardiovascular morbidity and mortality in controlled clinical trials (47). Moreover, the results of the Systolic Hypertension in the Elderly (SHEP) trial specifically showed the safety and efficacy of a diuretic and a b blocker in the treatment of isolated systolic hypertension in the elderly (48). In the elderly, a blanket recommendation for the starting medication in the treatment of hypertension is ill-advised, in part, because of the presence of comorbid conditions. For example, in older hypertensive patients with CHF and a reduced LV ejection fraction (49–53) or in those elderly patients with CHF with a normal LV ejection fraction (53–55), therapy should include a diuretic, an ACE inhibitor, and a b blocker.

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Loop diuretics remain first-line drug therapy in the treatment of patients with decompensated CHF. Diuretics are multifaceted in their effect in CHF. First, they effect a reduction in plasma volume by triggering a time-dependent natriuretic response. This drop in plasma volume reduces venous return and thereby decreases ventricular filling pressures. These volume changes facilitate relief of congestive symptomatology, such as peripheral and/or pulmonary edema. Intravenous loop-diuretic therapy has also been shown to increase central venous capacitance, which may further contribute to improvement in congestive symptomatology. Both loop and thiazide-like diuretics undergo a mixed pattern of renal or hepatic elimination with the component of renal clearance being responsible for diuresis (56). Age-related decreases in renal function may reduce the efficacy of conventional doses of diuretics in elderly patients. This “renal function-related resistance” can be easily overcome, if recognized, by careful upward titration of the diuretic dose. Resistance to diuretic effect in CHF may also derive from a pattern of variable and unpredictable absorption, particularly with the loop diuretic furosemide. This issue is resolvable with the use of a predictably absorbed loop diuretic such as torsemide (57). A thiazide-like diuretic, such as hydrochlorothiazide, may be used in the occasional older patient with mild CHF. However, thiazide-like diuretics have diminished effectiveness at conventional doses when the glomerular filtration rate falls below 30 mL/min; accordingly, older patients with moderate-to-severe CHF should be treated with a loop diuretic such as furosemide. Older patients with severe CHF or concomitant significant renal insufficiency may need combination diuretic therapy employing a loop diuretic together with the thiazide-like diuretic metolazone (56). The slowly and erratically absorbed form of metolazone (Zaroxylyn 1) is the preferred form when combination therapy is being considered. Nonsteroidal anti-inflammatory drugs (NSAIDs) may decrease both the antihypertensive and natriuretic effect of loop diuretics (56). This is a particular problem when loop diuretics are employed to manage CHF-related congestive symptomatology (58). A final consideration is the sometimes insidious manner by which NSAIDs can interact with diuretics in that several commonly used NSAIDs are now available over the counter. Serum electrolytes need to be closely monitored in older patients treated with diuretics. Hypokalemia and/or hypomagnesemia, both of which may precipitate ventricular arrhythmias and/or digitalis toxicity, can occur with diuretic therapy (59). Hyponatremia is not uncommon in the elderly treated with diuretics, particularly when thiazide-like diuretics are being employed (60). Older patients with CHF are especially sensitive to volume depletion with dehydration, hypotension, and prerenal azotemia occurring in the face of excessive diuretic effect. Older patients with CHF and normal LV ejection fraction should receive diuretics more cautiously. b-Adrenergic Blockers b Blockers are used in various cardiovascular disorders, with resultant beneficial and adverse effects (61). b Blockers are very effective antianginal agents in older, as well as younger, patients. Combined therapy with b blockers and nitrates may be more beneficial in the treatment of angina pectoris than either drug used alone (61). Diuretics or b blockers have been recommended as initial drug therapy for hypertension in older persons because these drugs have been shown to decrease cardiovascular morbidity and mortality in controlled clinical trials (47,62). b Blockers are especially useful in the treatment of hypertension in older patients who have had a prior MI, angina pectoris, silent myocardial ischemia, complex ventricular arrhythmias, supraventricular tachyarrhythmias, or hypertrophic cardiomyopathy.

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Teo et al. (63) analyzed 55 randomized controlled trials that investigated the use of b blockers in patients after MI. Mortality was significantly decreased (19%) in patients receiving b blockers, compared with control patients. In the Beta Blocker Heart Attack Trial (BHAT), propranolol significantly decreased total mortality by 34% in patients aged 60 to 69 years, and insignificantly reduced total mortality by 19% in patients aged 30 to 59 years (64). In the Norwegian Timolol Study, timolol significantly decreased total mortality by 43% in postinfarction patients aged 65 to 75 years, and significantly reduced total mortality by 34% in postinfarction patients younger than 65 years (65). Despite the utility of b blockers in post-MI patients, they are still underutilized in older patients (66–68). b Blockers decrease complex ventricular arrhythmias including ventricular tachycardia (69–72). b Blockers also increase the ventricular fibrillation threshold in animal models and have been shown to reduce the incidence of ventricular fibrillation in patients with acute MI (73). A randomized, double-blind, placebo-controlled study of propranolol in high-risk survivors of acute MI at 12 Norwegian hospitals demonstrated that patients treated with propranolol for one year had a statistically significant 52% decrease in sudden cardiac death (70). In addition, b blockers decrease myocardial ischemia (71,72,74), which may reduce the likelihood of ventricular fibrillation. Stone et al. (74) demonstrated by 48-hour ambulatory ECGs in 50 patients with stable angina pectoris that propranolol, not diltiazem or nifedipine, caused a significant decrease in the mean number of episodes of myocardial ischemia and in the mean duration of myocardial ischemia compared with placebo. Furthermore, b blockers reduce sympathetic tone. Studies have demonstrated that b blockers reduce mortality in older and younger patients with complex ventricular arrhythmias and heart disease (Table 4) (64,71,72,75–77). In the BHAT of 3290 patients comparing propranolol with placebo, propranolol reduced sudden cardiac death by 28% in patients with complex ventricular arrhythmias and by 16% in patients without ventricular arrhythmias (64). Hallstrom et al. (75) did a retrospective analysis of the effect of antiarrhythmic drug use in 941 patients resuscitated from prehospital cardiac arrest due to ventricular fibrillation between 1970 and 1985. b blockers were administered to 28% of the patients, and no antiarrhythmic drug to 39%. There was a reduced incidence of death or recurrent cardiac arrest in patients treated with b blockers versus no antiarrhythmic drug (relative risk 0.47; adjusted relative risk 0.62). Aronow et al. (76) performed a prospective study in 245 elderly patients (mean age 81 years) with heart disease (64% with prior MI and 36% with hypertensive heart disease), complex ventricular arrhythmias diagnosed by 24-hour ambulatory ECGs, and LV ejection fraction greater than 40%. Nonsustained ventricular tachycardia occurred in 32% of patients. Myocardial ischemia occurred in 33% of patients. Mean follow-up was 30 months in patients randomized to propranolol and 28 months in patients randomized to no antiarrhythmic drug. Propranolol was discontinued because of adverse effects in 11% of patients. Follow-up 24-hour ambulatory ECGs showed that propranolol was significantly more effective than no antiarrhythmic drug in reducing ventricular tachycardia (>90%), in decreasing the average number of ventricular premature complexes per hour (>70%), and in abolishing silent ischemia. Multivariate Cox regression analysis showed that propranolol caused a significant 47% decrease in sudden cardiac death, a significant 37% reduction in total cardiac death, and an insignificant 20% decrease in total death (71). Univariate Cox regression analysis showed that the reduction in mortality and complex ventricular arrhythmias in elderly patients with heart disease taking propranolol was due more to an anti-ischemic effect than to an antiarrhythmic effect (72). Table 4 also shows that there was a circadian

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Table 4 Effect of b Blockers on Mortality in Elderly Patients with Complex Ventricular Arrhythmias and Heart Disease Study

Age (yr)

Mean follow-up (mo)

BHAT

60–69 (33%)

25

Hallstrom

62 (mean)

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62–96 (mean 81)

29

Aronow et al.

62–96 (mean 81)

29

Aronow et al.

62–96 (mean 81)

29

CAST

66–79 (40%)

12

Results Compared with placebo, propranolol reduced sudden cardiac death by 28% in patients with complex VA and 16% in patients without VA. Reduced incidence of death or recurrent cardiac arrest in patients treated with b blockers vs. no antiarrhythmic drug (adjusted relative risk 0.62). Compared with no antiarrhythmic drug, propranolol caused a 47% significant decrease in sudden cardiac death, a 37% significant reduction in total cardiac death, and a 20% insignificant decrease in total death. Among patients taking propranolol, suppression of complex VA caused a 33% reduction in sudden cardiac death, a 27% decrease in total cardiac death, and a 30% reduction in total death; abolition of silent ischemia caused a 70% decrease in sudden cardiac death, a 72% reduction in total cardiac death, and a 69% decrease in total death. Incidence of sudden cardiac death or fatal myocardial infarction was significantly increased between 6 and 12 a.m., with peak hour at 8 a.m. and secondary peak at 7 p.m. in patients with no antiarrhythmic drug; propranolol abolished the circadian distribution of sudden cardiac death or fatal myocardial infarction. Patients on b blockers (30% of study group) had a significant reduction in all-cause mortality of 43% at 30 days, 46% at 1 year, and 33% at 2 years: in patients on b blockers, arrhythmic death or cardiac arrest was significantly reduced by 66% at 30 days, 53% at 1 year, and 36% at 2 years; multivariate analysis showed b blockers to be an independent factor for reduced arrhythmic death or cardiac arrest by 40% and for all-cause mortality by 33%.

Abbreviations: BHAT, Beta Blocker Heart Attack Trial; VA, ventricular arrhythmias; CAST, Cardiac Arrhythmia Suppression Trial. Source: From Refs. 64, 71, 72, 75–77, and 183.

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distribution of sudden cardiac death or fatal MI, with the peak incidence occurring from 6 a.m. to 12 a.m. (peak hour 8 a.m. and secondary peak around 7 p.m.) in patients treated with no antiarrhythmic drug (76) Propranolol abolished this circadian distribution of sudden cardiac death or fatal MI (76). In a retrospective analysis of data from the Cardiac Arrhythmia Suppression Trial (CAST), Kennedy et al. (77) found that 30% of patients with an LV ejection fraction less than 40% were receiving b blockers. Forty percent of these 1735 patients were between 66 and 79 years old. Patients on b blockers had a significant reduction in all-cause mortality of 43% within 30 days, 46% at one year, and 33% at two years. Patients receiving b blockers also had a significant decrease in arrhythmic death or cardiac arrest of 66% at 30 days, 53% at one year, and 36% at two years. Multivariate analysis showed that b blockers were an independent factor for reducing arrhythmic death or cardiac arrest by 40%, for decreasing all-cause mortality by 33%, and for reducing the occurrence of new or worsening CHF by 32%. On the basis of these data (64,71,72,75–77), b blockers can be utilized in the treatment of older and younger patients with ventricular tachycardia or complex ventricular arrhythmias associated with ischemic or nonischemic heart disease, and with normal or abnormal LV ejection fraction, if there are no absolute contraindications to the drugs. b Blockers are also useful in the treatment of supraventricular tachyarrhythmias in older and younger patients (78,79). If a rapid ventricular rate associated with atrial fibrillation persists at rest or during exercise despite digoxin therapy, then verapamil (80) diltiazem (81) or a b blocker (82) should be added to the therapeutic regimen. These drugs act synergistically with digoxin to depress conduction through the atrioventricular junction. The initial oral dose of propranolol is 10 mg q6h, which can be increased to a maximum of 80 mg q6h, if necessary. b Blockers have been demonstrated to reduce mortality in older persons with New York Heart Association (NYHA) class II-IV CHF and abnormal LV ejection fraction treated with diuretics and ACE inhibitors with or without digoxin (52,53,83–87). b Blockers have also been shown to reduce mortality in older persons with NYHA class II–III CHF and normal LV ejection fraction treated with diuretics plus ACE inhibitors (53,55,86,87). Numerous drug interactions have been reported with b blockers in the elderly (61). Recently, quinidine, a known inhibitor of CYP2D6, was shown to decrease the hepatic metabolism of topically applied ophthalmic timolol, with resultant exaggeration of the b-blocking effect of timolol (88). ACE Inhibitors ACE inhibitors are effective antihypertensive agents. A meta-analysis of 109 treatment studies showed that ACE inhibitors are more effective than other antihypertensive drugs in decreasing LV mass (89) Older hypertensive patients with CHF associated with abnormal (49–51) or normal (54) LV ejection fraction, LV hypertrophy, or diabetes mellitus, should initially be treated with an ACE inhibitor. ACE inhibitors reduce mortality in patients with CHF associated with abnormal LV ejection fraction (49–51). The Survival and Ventricular Enlargement (SAVE) trial (90) and the combined Studies of Left Ventricular Dysfunction (SOLVD) treatment and prevention trials (91) also demonstrated that ACE inhibitors such as captopril or enalapril should be standard therapy for most patients with significant LV systolic dysfunction with or without CHF. In addition, ACE inhibitor therapy has been shown to be beneficial in the treatment of elderly patients (mean age 80 years) with CHF caused by prior MI associated with normal LV ejection fraction (54). High-dose ACE inhibitor therapy remains the standard of care

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in the management of CHF. Low-dose ACE inhibitor therapy has been studied in CHF, but with less favorable results. For example, a recent trial compared low (2.5–5.0 mg/day) with high-dose lisinopril (32.5–35.0 mg/day), with the latter being associated with a more significant reduction in mortality and all-cause hospitalization rate (92). An observational prospective study was performed in 477 patients (mean age 79 years) with prior MI and an asymptomatic LV ejection fraction of less than 40% (mean LV ejection fraction 31%) (93). At 34-month follow-up, patients treated with ACE inhibitors without b blockers had a 17% significant reduction in new coronary events and a 32% significant reduction in CHF. (93). At 34-month follow-up, patients treated with b blockers without ACE inhibitors had a 25% significant reduction in new coronary events and a 41% significant reduction in CHF (93). At 41-month follow-up, patients treated with both b blockers and ACE inhibitors had a significant 37% reduction in new coronary events and a significant 60% reduction in CHF (93). Treatment with ACE inhibitors should be initiated in elderly patients in low doses after correction of hyponatremia or volume depletion. It is important to avoid overdiuresis before beginning therapy with ACE inhibitors since volume depletion may cause hypotension or renal insufficiency when ACE inhibitors are begun or when the dose of these drugs is increased to full therapeutic levels. After the maintenance dose of ACE inhibitor is reached, it may be necessary to increase the dose of diuretics. The initial dose of enalapril is 2.5 mg daily and of captopril is 6.25 mg TID. The maintenance doses are 5 to 20 mg daily and 25 to 50 mg TID, and the maximum doses are 20 mg BID and 150 mg TID, respectively. Older patients at risk for excessive hypotension should have their blood pressure monitored closely for the first two weeks of ACE inhibitor or angiotensin II receptor blocking therapy, and, thereafter, whenever the dose of ACE inhibitor or diuretic is increased. Renal function should be monitored in patients on ACE inhibitors to detect increases in blood urea nitrogen and serum creatinine, especially in older patients with renal artery stenosis. A rise in serum creatinine in an ACE inhibitor treated CHF patient is not uncommonly the result of ACE inhibitor-induced alterations in renal hemodynamics. There is no specific rise in serum creatinine where corrective actions need be taken though logic would suggest that the greater the increment in serum creatinine the more important the intervention. Typically, reducing or temporarily discontinuing diuretics and/ or liberalizing sodium intake are sufficient measures to return renal function to baseline. Not uncommonly though, the administered ACE inhibitor is either stopped or the dose reduced. In most instances, ACE inhibitor therapy can be safely resumed as long as careful attention is paid to patient volume status (94). Potassium-sparing diuretics or potassium supplements should be carefully administered to patients receiving ACE inhibitor therapy because of the attendant risk of hyperkalemia. In this regard, the Randomized Aldactone Evaluation Study (RALES) showed in persons with severe CHF treated with diuretics, ACE inhibitors, and digoxin that compared with placebo, spironolactone 25 mg/day did not carry an excessive risk of hyperkalemia while resulting in a significant reduction in mortality and hospitalization for CHF (95). Angiotensin-II Receptor Blockers Angiotensin-II receptor blockers (ARBs) have been studied fairly extensively in hypertension (96–98), diabetic nephropathy (99), and CHF (100), with results comparable to those seen when these disease states are treated with ACE inhibitors. Although the published experience with these drugs in the elderly is limited, the drugs appear to be safe if used with similar precautions as those recommended for ACE inhibitors, as described above (96,98). These drugs are noteworthy in that they have a more favorable side-effect profile

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and, in particular, are not associated with cough, a fairly common side effect with ACE inhibitor therapy (97). Likewise, in the Losartan Heart Failure Survival Study (ELITE II), losartan was associated with fewer adverse effects than was captopril (101). Outcomes of studies are supportive of ARBs, such as losartan and irbesartan, being superior to conventional non-ACE-inhibitor-based therapy in decreasing end-stage renal failure event rates in patients with type II diabetic nephropathy (102,103). In CHF the hope that ARBs are more effective therapy than ACE inhibitors has not been realized, as of yet, though additional studies are underway to establish the positioning of ARBs in current HF regimens. Direct Renin Inhibitors Aliskiren is a nonpeptide direct renin inhibitor and is the first drug of this class to be approved for clinical use in systemic hypertension (see chapter 5, “Systemic Hypertension in the Elderly”) (104). The drug is approved for once-daily use as a monotherapy and for combination use with other antihypertensive drugs. There is no dose adjustment necessary in elderly patients or in patients with hepatic or renal insufficiency (105). The most common side effects of aliskiren are a lower incidence of headache, nasopharyngitis, dizziness, and diarrhea. The drug is not associated with an increased incidence of cough (106). Angioedema is a rare complication of therapy and appears to occur at a lower frequency than with ACE inhibitors (106). Pharmacokinetic studies with aliskiren have shown no relevant drug-drug interactions with warfarin, digoxin, amlodipine, valsartan, and ramipril (107,108). With the combination of aliskiren and furosemide, there are decreased levels of the diuretic (105). Nitrates Nitrates are effective therapies for older individuals; however, caution should always be used because of the associated dangers of orthostatic hypotension, syncope, and falls, especially if the treatment is combined with diuretics and other vasodilators. Recently, it was shown that nitrate headaches are less frequent in older patients and in individuals with renal dysfunction (109). It has also been shown that the use of the thiazolidinedione rosiglitazone may increase the risk of myocardial ischemia in patients taking concomitant nitrate therapy. Calcium Channel Blockers Calcium channel blockers are effective antihypertensive and antianginal drugs in older patients. Verapamil (80) and diltiazem (81) are especially valuable in treating hypertensive patients who also have supraventricular tachyarrhythmias. However, recent reports have suggested an increased mortality risk with calcium channel blockers, especially with the use of short-acting dihydropyridines in older subjects (110–112). With the use of longer-acting calcium blockers, such as the dihydropyridine nitrendipine, a strong mortality benefit was seen in patients with isolated systolic hypertension (113), although many were receiving concurrent b-blocker therapy. In contrast, nisoldipine was shown to be less effective in protecting against cardiovascular mortality in diabetic patients with hypertension when compared with an enalapril-treated group (114). Verapamil improved exercise capacity, peak LV filling rate, and a clinicoradiographic HF score in patients with CHF, normal LV ejection fraction, and impaired LV diastolic filling (115). However, calcium channel blockers, such as verapamil, diltiazem, and nifedipine, may exacerbate CHF in patients with associated abnormal LV ejection fraction (116). In addition, some calcium channel blockers have been shown to increase mortality in

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patients with CHF and abnormal LV ejection fraction after MI (117). Therefore, calcium channel blockers such as verapamil, diltiazem, and nifedipine may be used to treat older patients with CHF associated with normal LV ejection fraction, but are contraindicated in treating older patients with CHF associated with abnormal LV ejection fraction. Amlodipine and felodipine are two vasculospecific dihydropyridine agents that appear to be safer in patients having CHF, although neither of these drugs should be used to treat CHF(28). The age-associated decrease in hepatic blood flow and hepatic metabolic capacity may result in higher serum concentrations of verapamil, diltiazem, and nifedipine (118). Therefore, these drugs should be given to older persons in lower starting doses and titrated carefully. a-Adrenergic Blockers a-Adrenergic blockers are effective treatments for patients with hypertension and have become first-line treatments for males with symptomatic prostatism. Caution should be exercised when using these agents because of a significant incidence of postural hypotension, especially in patients receiving diuretics or other vasodilator drugs (119,120). A more selective a1 blocker, tamsulosin, is now available, which improves prostatism symptoms without having vasodilator effects (121). However, the National Heart, Lung, and Blood Institute withdrew doxazosin from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack (ALLHAT) trial after an interim analysis showed a 25% greater rate of a secondary endpoint, combined cardiovascular disease in patients on doxazosin than in those on chlorthalidone, largely driven by the increased risk of CHF (122). These findings have cast a shroud over the use of doxazosin in the elderly, particularly if it is being contemplated as monotherapy in a hypertensive elderly patient. Lidocaine Intravenous lidocaine may be used to treat complex ventricular arrhythmias during acute MI (78). Lidocaine toxicity is more common in the elderly and older patients should be monitored for dose-related confusion, tinnitus, paresthesias, slurred speech, tremors, seizures, delirium, respiratory depression, and hypotension. Older patients with CHF or impaired liver function are at increased risk for developing central nervous system adverse effects from lidocaine (123). In these patients, the loading dose should be decreased by 25–50%, and any maintenance infusion should be initiated at a rate of 0.5 to 2.5 mg/min, with the patient monitored closely for adverse effects. The dose of lidocaine should also be reduced if the patient is receiving b blockers (124) or cimetidine, since these drugs reduce the metabolism of lidocaine. Other Antiarrhythmic Drugs The use of antiarrhythmic drugs in the elderly is extensively discussed elsewhere (79,125). In the CAST I trial, encainide and flecainide significantly increased mortality in survivors of MI with asymptomatic or mildly symptomatic ventricular arrhythmias, when compared with placebo (126). In the CAST II, moricizine insignificantly increased mortality when compared with placebo (127). Akiyama et al. (128) found that older age increased the likelihood of adverse events, including death, in patients treated with encainide, flecainide, or moricizine in these two studies. In a retrospective analysis of the effect of empirical antiarrhythmic treatment in 209 cardiac arrest patients who were resuscitated out of hospital, Moosvi et al. (129)

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found that the two-year mortality was significantly lower for patients treated with no antiarrhythmic drug than for patients treated with quinidine or procainamide. Hallstrom et al. (75) showed an increased incidence of death or recurrent cardiac arrest in patients treated with quinidine or procainamide versus no antiarrhythmic drug. In a prospective study of 406 elderly subjects (mean age 82 years) with heart disease (58% with prior MI) and asymptomatic complex ventricular arrhythmias, the incidence of sudden cardiac death, total cardiac death, and total mortality were not significantly different in patients treated with quinidine or procainamide or with no antiarrhythmic drug (130). In this study, quinidine or procainamide did not reduce mortality in comparison with no antiarrhythmic drug in elderly patients with presence versus absence of ventricular tachycardia, ischemic or nonischemic heart disease, and abnormal or normal LV ejection fraction. The incidence of adverse events causing drug cessation in elderly patients in this study was 48% for quinidine and 55% for procainamide. A meta-analysis of six double-blind studies of 808 patients with chronic atrial fibrillation who underwent direct current cardioversion to sinus rhythm demonstrated that the one-year mortality was significantly higher in patients treated with quinidine than in patients treated with no antiarrhythmic drug (131). In the Stroke Prevention in Atrial Fibrillation Study, arrhythmic death and cardiac mortality were also significantly increased in patients receiving antiarrhythmic drugs compared with patients not receiving antiarrhythmic drugs, especially in patients with a history of CHF (132). Teo et al. (63) analyzed 59 randomized controlled trials comprising 23,229 patients that investigated the use of class I antiarrhythmic drugs after MI. Patients receiving class I antiarrhythmic drugs had a significantly higher mortality than patients receiving no antiarrhythmic drugs. None of the 59 trials demonstrated that a class I antiarrhythmic drug decreased mortality in postinfarction patients. Therefore, it is currently not recommended that class I antiarrhythmic drugs be used for the treatment of ventricular tachycardia or complex ventricular arrhythmias associated with heart disease. Amiodarone is very effective in suppressing ventricular tachycardia and complex ventricular arrhythmias. However, there are conflicting data about the effect of amiodarone on mortality (133–140). The Veterans Administration Cooperative Study comparing amiodarone versus placebo in HF patients with malignant ventricular arrhythmias recently showed that amiodarone was very effective in decreasing ventricular tachycardia and complex ventricular arrhythmias, but it did not affect mortality (139). In the Sudden Cardiac Death in Heart Failure Trial, 2521 patients, mean age 60 years, with NYHA class II or III HF, a LV ejection fraction of 35% or less and a mean QRS duration on the resting ECG of 120 milliseconds, were randomized to placebo, amiodarone, or an implantable cardioverter-defibrillator (ICD) (140). At 46-month median follow-up, compared with placebo, amiodarone insignificantly increased mortality by 6% but ICD therapy significantly reduced all-cause mortality by 23% (140). The incidence of adverse effects from amiodarone has been reported to approach 90% after five years of treatment (141). In the Cardiac Arrest in Seattle: Conventional Versus Amiodarone Drug Evaluation Study, the incidence of pulmonary toxicity was 10% at two years in patients receiving an amiodarone dose of 158 mg daily (142). On the basis of these data, one should reserve the use of amiodarone for the treatment of lifethreatening ventricular tachyarrhythmias or in patients who cannot tolerate or who do not respond to b-blocker therapy. Amiodarone is also the most effective drug for treating refractory atrial fibrillation in terms of converting atrial fibrillation to sinus rhythm and slowing a rapid ventricular rate. However, because of the high incidence of adverse effects caused by amiodarone, it

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should be used in low doses in patients with atrial fibrillation when life-threatening atrial fibrillation is refractory to other therapy (143). Lipid-Lowering Drugs The safety of lipid-lowering drugs, specifically 3-hydroxy-3-methylglutaryl-coenzyme A (HMG CoA) reductase inhibitors (statins), was demonstrated in the Cholesterol Reduction in Seniors Program (CRISP) (144). Furthermore, a meta-analysis of 14 randomized trials of statins from 90,056 participants confirmed the safety and efficacy of statins (145). In the Scandinavian Simvastatin Survival Study, 1,464,444 men and women with coronary artery disease were treated with double-blind simvastatin or placebo. At 5.4-years follow-up, patients treated with simvastatin had a 35% decrease in serum low-density lipoprotein (LDL) cholesterol, a 25% reduction in serum total cholesterol, an 8% increase in serum high-density lipoprotein (HDL) cholesterol, a 34% decrease in major coronary events, a 42% reduction in coronary deaths, and a 30% decrease in total mortality. In patients aged 65 to 70 years, simvastatin reduced all-cause mortality by 35%, coronary artery disease mortality by 43%, major coronary events by 34%, nonfatal MI by 33%, any atherosclerosis-related endpoint by 34%, and coronary revascularization by 41% (147). The absolute risk reduction for both all-cause mortality and coronary artery disease mortality was approximately twice as great in persons aged 65 to 70 years compared with persons younger than 65 years (147). In the Cholesterol and Recurrent Events Trial (148), 4159 men and women aged 21 to 75 years (1283 aged 65–75 years) with MI, serum total cholesterol levels less than 250 mg/dL, and serum LDL cholesterol levels greater than or equal to 115 mg/dL were treated with double-blind pravastatin and placebo. At five-year follow-up, patients treated with pravastatin had a 32% reduction in serum LDL cholesterol, a 20% decrease in serum total cholesterol and a 5% increase in serum HDL cholesterol. Pravastatin reduced coronary artery disease death or nonfatal MI significantly by 39% in persons aged 65 to 75 years, and insignificantly by 13% in persons younger than 65 years (148). Pravastatin decreased major coronary events significantly by 32% in persons aged 65 to 75 years and significantly by 19% in persons younger than 65 years. It also reduced stroke significantly by 40% in persons aged 65 to 75 years and insignificantly by 20% in persons younger than 65 years. Pravastatin decreased coronary revascularization significantly by 32% in persons aged 65 to 75 years, and significantly by 25% in persons younger than 65 years. For every 1000 persons treated with pravastatin for five years, 225 cardiovascular events would be prevented in persons aged 65 to 75 years and 121 cardiovascular events would be prevented in persons younger than 65 years (148). In the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) trial, a randomized, placebo-controlled study of 5804 men and 3000 women, pravastatin 40 mg/day was shown to lower LDL concentrations by 34% in subjects 70 to 82 years of age. In this study, drug treatment reduced coronary heart disease death (CHD) and nonfatal MI. No benefit on stroke prevention was seen, and there were more cancer diagnoses with pravastatin. However, incorporation of this latter finding in a meta-analysis showed no overall increase in cancer risk (149). The Long-Term Intervention with Pravastatin in Ischaemic Disease study randomized 9014 persons with a history of MI or unstable angina who had initial serum total cholesterol levels of 155 to 271 mg/dL to pravastatin 40 mg daily or placebo (150). At eight-year follow-up of 3514 persons aged 65 to 75 years at study entry, compared with placebo, pravastatin significantly reduced all-cause mortality by 21%, death from CHD by 24%, fatal

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and nonfatal MI by 26%, death from cardiovascular disease by 26%, need for coronary artery bypass graft surgery by 26%, and need for coronary angioplasty by 34% (150). The Heart Protection Study randomized 20,536 men and women (5806 of whom were aged 70–80 years) with prior MI (8510 persons), other CHD (4876 persons), and no CHD (7150 persons) and a serum total cholesterol level of 135 mg/dL or higher to simvastatin 40 mg daily or to placebo (151). Of the 7150 persons without CHD, 25% had cerebrovascular disease, 38% had peripheral arterial disease (PAD), 56% had diabetes mellitus, and 3% had only treated hypertension without atherosclerotic vascular disease or diabetes mellitus. At five-year follow-up, compared with placebo, simvastatin significantly reduced all-cause mortality by 13%, any cardiovascular death by 17%, major coronary events by 27%, any stroke by 25%, coronary or noncoronary revascularization by 24%, and any major cardiovascular event by 24% (151). These significant reductions in mortality and in cardiovascular events occurred regardless of initial levels of serum lipids, age, or gender. First major cardiovascular event was significantly reduced by simvastatin by 24% in persons younger than 65 years, by 23% in persons aged 65 to 69 years, and by 18% in persons aged 70 to 80 years at study entry (151). Five years of simvastatin treatment prevented MI, stroke, and revascularization in 70 to 100 persons per 1000 treated persons (151). Sixty-nine elderly patients, mean age 75 years, with intermittent claudication due to PAD were randomized to simvastatin 40 mg daily or placebo (152). Compared with placebo, simvastatin significantly increased treadmill exercise time until the onset of intermittent claudication by 24% at six months after treatment and by 42% at one year after treatment. Observational data have also demonstrated in 1410 men and women, mean age 81 years, with CHD and hypercholesterolemia that at three-year follow-up, use of statins significantly reduced CHD death or nonfatal MI by 50% (153), stroke by 60% (154), and CHF by 48% (155). The lower the reduction in serum LDL cholesterol, the greater the reduction in coronary events (153) and in stroke (154). Statins also significantly reduced new coronary events by 37% and new stroke by 47% in 529 men and women, mean age 79 years, with diabetes mellitus, prior MI, and hypercholesterolemia at 29-month followup (156). In addition, statins significantly reduced new coronary events by 52% in persons with prior MI and by 59% in persons with no prior MI in 660 men and women with PAD and hypercholesterolemia at 39-month follow-up (157). On the basis of the available data showing increased risk of cardiovascular disease from abnormal lipoprotein patterns (158), dietary therapy for older patients with dyslipidemia, regardless of age, in the absence of other serious life-limiting illnesses, such as cancer, dementia, or malnutrition, is recommended (159). If hyperlipidemia persists after three months of dietary therapy, hypolipidemic drugs should be considered, depending on serum lipid levels, presence or absence of coronary artery disease, presence or absence of other coronary risk factors, and the patient’s overall clinical status. This approach is consistent with the recent National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults recommendations in males aged 65 years and older and females aged 75 years and older. (160). In older men and women, the HMG-CoA reductase inhibitors would be the drugs of choice for treating a high-serum LDL cholesterol level. Recent data have demonstrated that the serum LDL cholesterol should be reduced to less than 70 mg/dL in high-risk persons regardless of age or gender (161–163). The updated National Cholesterol Education Program (NCEP) III guidelines state that in very high-risk patients, a serum LDL cholesterol level of less than 70 mg/dL is a reasonable clinical strategy (164). When a high-risk person has hypertriglyceridemia or low serum HDL cholesterol, consideration can be given to combining a fibrate or nicotinic acid with an LDL cholesterol–lowering drug (164). For moderately high-risk persons (two or more

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risk factors and a 10-year risk for CHD of 10% to 20%), the serum LDL cholesterol should be reduced to less than 100 mg/dL (164). When LDL cholesterol–lowering drug therapy is used to treat high-risk persons or moderately high-risk persons, the serum LDL cholesterol should be reduced by at least 30–40% (164). Anticoagulants Anticoagulant therapy in the elderly is discussed extensively elsewhere (79,165) Anticoagulants are effective in the prevention and treatment of many thromboembolic disorders including venous thromboembolism and pulmonary embolism, acute MI and embolism associated with prosthetic heart valves or atrial fibrillation. These conditions, necessitating the use of anticoagulants, are more common in elderly than in younger patients. In the report from the Sixty Plus Reinfarction Group who evaluated the effects of oral anticoagulant therapy on total mortality after MI in patients older than 60 years, it was shown that active therapy lowered both mortality and reinfarction compared with placebo (166). However, the treatment group also had more major bleeding complications. The anticoagulant response to warfarin is increased with age (167). Chronic diseases, which increase the risk for bleeding during anticoagulant therapy, are also more common in elderly patients than in younger patients. In addition, elderly patients are at higher risk for bleeding during anticoagulant therapy because of increased vascular or endothelial fragility (168). Furthermore, older patients may be at increased risk for bleeding due to anticoagulant therapy because they may be taking other drugs that potentiate the anticoagulant effect. Drugs such as aspirin, cephalosporins, and penicillins increase the risk of bleeding in patients treated with heparin. Drugs such as allopurinol, amiodarone, aspirin, cimetidine, ciprofloxacin, clofibrate, cotrimoxazole, dextroproproxyphene, disulfiram, erythromycin, fluconazole, isoniazid, ketoconazole, meclofenamic acid, metronidazole, miconazole, norfloxacin, phenylbutazone, phenytoin, quinidine, sulfinpyrazone, sulindac, thyroxine, and trimethoprim-sulfamethoxazole potentiate the effect of warfarin, causing an increased prothrombin time and risk of bleeding. ADVERSE EFFECTS OF DRUGS IN THE ELDERLY Cardiovascular drugs are often associated with adverse effects that simulate common disorders in the elderly (Table 5). In addition, there are important drug-disease interactions (Table 6), drug-drug interactions (Table 7), and drug-alcohol interactions (169) (Table 8) that occur in older patients. Table 5 Cardiovascular Drugs Regularly Detected as the Culprit in Some Common Disorders of the Elderly Disorder

Drugs

Confusion states Tinnitus, vertigo Depression Falls Postural hypotension Constipation Urinary retention Urinary incontinence

b blockers, digoxin, methyldopa and related drugs, quinidine Aspirin, furosemide, ethacrynic acid b blockers, methyldopa, reserpine All drugs liable to produce postural hypotension, glycerol trinitrates All antihypertensives, antianginal drugs, b blockers, diuretics Anticholinergics, clonidine, diltiazem, diuretics, verapamil Disopyramide, midodrine b blockers, diuretics, labetalol, prazosin

Source: From Ref. 181.

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Table 6 Important Drug-Disease Interactions in Geriatric Patients Underlying disease

Drugs

Adverse effect

b blockers, verapamil, NSAIDs and thiazolidinediones Ischemic heart disease NSAIDs, rosiglitazone Cardiac conduction disorders Tricyclic antidepressants Hypertension NSAIDs Peripheral vascular disease b blockers Chronic obstructive b blockers pulmonary disease Chronic renal impairment NSAIDs, contrast agents, aminoglycosides, ACE inhibitors Diabetes mellitus Diuretics Prostatic hypertrophy Drugs with antimuscarinic side effects Depression b blockers, centrally acting antihypertensives Hypokalemia Digoxin Peptic ulcer disease Anticoagulants, salicylates

Congestive heart failure

Acute cardiac decompensation Increased ischemic events Heart block Increased blood pressure Intermittent claudication Bronchoconstriction Acute renal failure Hyperglycemia Urinary retention Precipitation or exacerbation of depression Cardiac arrhythmias GI hemorrhage

Abbreviations: NSAID, nonsteroidal anti-inflammatory drug; GI, gastrointestinal. Source: From Ref. 184.

Table 7 Selected Clinically Significant Drug-Drug Interactions in Geriatric Patients Mechanism of interaction

Primary drugs

Interacting drugs

Possible effects

Augmented drug effects Antidiabetic sulfonylureas (tolbutamide, chlorpropamide) Azathioprine Carbamazepine

Chloramphenicol, Warfarin, Phenylbutazone Quinidine Allopurinol Diltiazem, verapamil

IM IM, DP, IE OM

Hypoglycemia

IM IM

Cyclosporine

Diltiazem, verapamil

IM

Digoxin

Amiodarone, diuretics, quinidine, verapamil

OM

Disopyramide Lidocaine

Diltiazem, verapamil b blockers, cimetidine

OM HBF

Bone marrow suppression Increase serum carbamazepine concentration and risk of toxicity (e.g., nausea, ataxia, nystagmus) Increase serum cyclosporine concentration and risk of toxicity (e.g., hepato- and nephrotoxicity) Increase serum digoxin concentration and risk of toxicity (e.g., nausea, confusion, cardiotoxicity) Bradycardia Increase serum lidocaine concentration and risk of toxicity (e.g., sedation, seizures, cardiotoxicity)

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Table 7 Selected Clinically Significant Drug-Drug Interactions in Geriatric Patients (Continued ) Primary drugs

Interacting drugs

Methotrexate

Aspirin, indomethacin, phenylbutazone Probenecid Sulfisoxazole Diltiazem, verapamil Cimetidine Diltiazem, verapamil Amiodarone, chloramphenicol, cimetidine, fluconazole, isoniazid, phenylbutazone Valproic acid, warfarin Diltiazem, Verapamil

Procainamide Propranolol Phenytoin

Quinidine

Warfarin

Mechanism of interaction

Possible effects

DP, IE

Bone marrow suppression

IE DP OM HBF OM IM

DP, IM IM

Aspirin, indomethacin DP Amiodarone, cimetidine, IM metronidazole Phenylbutazone, DP, IM sulfonamides

Decreased drug effects All medications

Cholestyramine

Antidiabetic sulfonylureas (tolbutamide, chlorpropamide) Digoxin

IIS, MCM, b Blockers IIR (nonselective) Corticosteroids, thiazide OM diuretics Sucralfate IA

Lincomycin Phenytoin

Kaolin-pectin Calcium, Sucralfate

IA IA

Prednisone Quinidine

Rifampin Barbiturates Barbiturates, rifampin

SM SM SM

Antacids-Iron Barbiturates, carbamazepine, glutethimide, rifampin vitamin K

IA SM

Tetracycline Warfarin

IA

Bradycardia Bradycardia Bradycardia, hypotension Increase serum phenytoin concentration and risk of toxicity (e.g., nystagmus, sedation) Increase serum quinidine concentration and risk of toxicity (e.g., nausea, cinchonism, arrhythmias) Hemorrhage

Delay or reduce absorption of other drugs. Administer other drugs 1–2 hrs before or 4–6 hrs after cholestyramine Decrease hypoglycemic effects

Reduce absorption of digoxin. Administer sucralfate at least 2 hrs apart from digoxin. Decrease drug bioavailability Decrease serum phenytoin concentration and anticonvulsant effect Decreased steroid effects Decrease antiarrhythmic effect Decrease drug bioavailability Loss of anticoagulant control

SP

(Continued )

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Table 7 Selected Clinically Significant Drug-Drug Interactions in Geriatric Patients (Continued ) Primary drugs

Interacting drugs

Other drug effects ACE Inhibitors

HMG-CoA reductase inhibitors

Potassium-sparing diuretics, potassiumcontaining medications Cyclosporine, gemfibrozil, niacin Erythromycin

Mechanism of interaction

Possible effects

RAP

Hyperkalemia

Unknown

Rhabdomyolysis, acute renal failure

IM

Abbreviations: IM, inhibition of drug metabolism; DP, displacement of protein binding; IE, inhibition of renal excretion; OM, other mechanisms (pharmacodynamic effects of drugs on tissue responses); HBF, decreased hepatic blood flow; IA, inhibition of drug absorption; IIS, inhibition of insulin secretion; MCM, modification of carbohydrate metabolism; IIR, increased peripheral insulin resistance; SM, stimulation of drug metabolism; SP, increased hepatic synthesis of procoagulant factors; RAP, reduction of aldosterone production; HMG-CoA, 3-hydroxy-3-methylglutaryl-coenzyme A. Source: From Ref. 185.

Table 8 Selected Clinically Significant Drug-Alcohol Interactions in Geriatric Patients Primary drugs

Interacting drug

Possible effects

Antidiabetic sulfonylureas ACE inhibitors Isoniazid

Alcohol

Disulfiram-like reactions (especially with chlorpropamide)

Alcohol Alcohol

Nitrates Phenytoin

Alcohol Alcohol

Rifampin

Alcohol

SedativesHypnotics Vitamins Warfarin

Alcohol

Hypotension Decreased therapeutic effect of isoniazid, increased risk of hepatic toxicity Hypotension Decreased serum phenytoin concentration and effectiveness (chronic use of alcohol); increased serum phenytoin concentration and risk of toxicity (acute intake of alcohol) Decreased therapeutic effect of rifampin, increased risk of hepatic toxicity Excessive sedation

Alcohol Alcohol

Decreased absorption and storage of folic acid and thiamine Increased anticoagulant activity (acute intoxication); decreased anticoagulant activity (chronic abuse)

Abbreviation: ACE, angiotensin-converting enzyme. Source: From Ref. 186.

MEDICATIONS BEST TO AVOID IN THE ELDERLY Careful selection of drugs and dosages of drugs in the elderly can minimize adverse outcomes while maximizing clinical improvement. In their first attempt to identify medications and doses of medication that may be best to avoid in the elderly, Beers and colleagues developed a set of explicit criteria after an extensive review of the literature and assistance from 13 well-recognized experts in geriatric medicine and pharmacology (170). These criteria included 30 statements that described medications that should

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generally be avoided in nursing home residents, as well as statements that described doses, frequencies, and duration of medications that should generally not be exceeded. Since the publication of the explicit criteria, several research studies have utilized these criteria to evaluate the appropriateness of medication prescribing in the elderly (171–174). The most striking study of this type was performed by Willcox and colleagues (174), who reported a potentially inappropriate medication prescription in 23.5% of elderly in the community. They were criticized, however, for applying criteria that were designed for frail elderly patients in nursing homes to healthier elderly residents in the community, along with criteria that need to be updated (175). Acknowledging the limitation of this first set of criteria, Beers updated and expanded it to encompass elderly patients who are in the ambulatory setting, as well as medications that should be avoided in elderly known to have certain conditions (176). With the assistance of six nationally recognized experts in geriatric medicine and pharmacology, a set of 63 criteria was developed using the first set of criteria and a more recent literature review. Of the 63 criteria, 28 described medications or categories of medication that were considered to be potentially inappropriate when used by all older patients and 35 described medications or categories of medications that were considered to be potentially inappropriate when used by elderly patients with any of 15 known medical conditions such as heart failure, diabetes, hypertension, asthma, and arrhythmias. These criteria were further rated by the six panelists regarding their importance. The panelists considered a criterion to be severe when an adverse outcome was both likely to occur and, if it did occur, would likely lead to a clinically significant event (176). Table 9 lists the cardiac medications that were recognized by the expert panel as having the highest severity of potential problems occurring from their use and the reasons for their avoidance. Table 10 lists medications that were identified by the expert panel as having the highest severity of potential problems and the reasons for their avoidance in the elderly when certain cardiac-related conditions exist. Although these criteria serve as useful tools for assessing the quality of prescribing to the elderly, they do not identify all cases of potentially inappropriate prescribing. In fact, these criteria may identify appropriate prescribing as inappropriate at times. The latter case may particularly be likely when physicians and pharmacists carefully adjust medication regimens for specific needs of individual patients (176). Table 9 Medications to Avoid in Older Patients Medications

Prescribing concerns

Disopyramide

Of all antiarrhythmics, disopyramide is the most potent negative inotrope and therefore may induce heart failure in the elderly. It is also strongly anticholinergic. When appropriate, other antiarrhythmic drugs should be used. Because of decreased renal clearance of digoxin, doses in the elderly should rarely exceed 0.125 mg daily, except when treating atrial arrhythmias. Methyldopa may cause bradycardia and exacerbate depression in the elderly. Alternate treatments for hypertension are generally preferred. Ticlopidine has been shown to be no better than aspirin in preventing clotting and is considerably more toxic. Avoid in the elderly.

Digoxina

Methyldopaa & methyldopa/HCTZa Ticlopidine a

Panelists believed that the severity of adverse reaction would be substantially greater when these drugs were recently started. In general, the greatest risk would be within about a one-month period. Abbreviation: HCTZ, hydrochlorothiazide. Source: From Ref. 187.

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Table 10 Medications to Avoid in Older Patients with Specific Diseases and Conditions Diseases/conditions

Medications

Prescribing concerns

Heart failure

Disopyramide

Hypertension Blood-clotting disorders, limited to those receiving anticoagulant Syncope or falls Arrhythmias

Diet pills; amphetamines Aspirin, NSAIDs, dipyridamole, and ticlopidine

Negative inotrope; may worsen heart failure May elevate blood pressure May cause bleeding in those using anti-coagulants therapy

Long-acting benzodiazepine drugs May contribute to falls Tricyclic antidepressant drugsa May induce arrhythmias

a

Panelists believed that the severity of adverse reaction would be substantially greater when these drugs were recently started. In general, the greatest risk would be within about a one-month period. Abbreviation: NSAID, nonsteroidal anti-inflammatory drug. Source: From Ref. 187.

PRUDENT USE OF MEDICATION IN THE ELDERLY Although the elderly make up only 14% of our population, they receive more than 30% of all prescribed medication (177). The increased exposure of medications in the elderly may lead to higher incidence of adverse drug reactions and drug-drug interactions in this population (178). Physiologic changes with aging may also alter the elimination of drugs that can contribute to adverse outcomes with medication usage. With these concerns in mind, several authors have suggested some steps that clinicians may employ to ensure safe prescribing (177,179,180). These suggestions include the following. l l

l l l l l l l l

Acquire a full history of the patient’s habits and medication use. Evaluate the need for drug therapy. Consider alternative non–drug approaches when appropriate. Know the pharmacology of the drugs prescribed. Start with low dose of medication and titrate up slowly. Titrate medication dosage according to the patient’s response. Minimize the number of medications used. Educate patients regarding proper usage of medications. Be aware of medication cost, which may have an impact on compliance. Provide patient with a portable prescription record. Review the treatment plan regularly and discontinue medications no longer needed.

With proper monitoring and adequate understanding of the effects of medications in the elderly, the use of medication can be a positive experience for both the elderly patient and the clinician. REFERENCES 1. Cusack BJ, Vestal RE. Clinical pharmacology: special considerations in the elderly. In: Calkins E, Davis PJ, Ford AB, eds. Practice of Geriatric Medicine. Philadelphia, PA: WB Saunders, 1986:115–134. 2. Levine WG, Frishman WH: Basic principles of clinical pharmacology relevant to cardiology. In: Frishman WH, Sonnenblick EH, Sica D, eds. Cardiovascular Pharmacotherapeutics. 2nd ed. New York, NY: McGraw-Hill, 2003:3–13.

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153. Aronow WS, Ahn C. Incidence of new coronary events in older persons with prior myocardial infarction and serum low-density lipoprotein cholesterol 125 mg/dL treated with statins versus no lipid-lowering drug. Am J Cardiol 2002; 89:67–69. 154. Aronow WS, Ahn C, Gutstein H. Incidence of new atherothrombotic brain infarction in older persons with prior myocardial infarction and serum low-density lipoprotein cholesterol 125 mg/dL treated with statins versus no lipid-lowering drug. J Gerontol: Med Sci 2002; 57A:M333–M335. 155. Aronow WS, Ahn C. Frequency of congestive heart failure in older persons with prior myocardial infarction and serum low-density lipoprotein cholesterol 125 mg/dl treated with statins versus no lipid-lowering drug. Am J Cardiol 2002; 90:147–149. 156. Aronow WS, Ahn C, Gutstein H. Reduction of new coronary events and of new atherothrombotic brain infarction in older persons with diabetes mellitus, prior myocardial infarction, and serum low-density lipoprotein cholesterol 125 mg/dL treated with statins. J Gerontol: Med Sci 2002; 57A:M747–M750. 157. Aronow WS, Ahn C. Frequency of new coronary events in older persons with peripheral arterial disease and serum low-density lipoprotein cholesterol 125 mg/dl treated with statins versus no lipid-lowering drug. Am J Cardiol 2002; 90:789–791. 158. Zimetbaum P, Frishman WH, Ooi WL, et al. Plasma lipids and lipoproteins and the incidence of cardiovascular disease in the old: Bronx Longitudinal Aging Study. Arterio Thrombo 1992; 12:416–423. 159. Collins R, Armitage J. High-risk elderly patients PROSPER from cholesterol-lowering therapy. Lancet 2002; 360:1618–1619 (commentary). 160. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA. 2001; 285:2486–2497. 161. Nissen SE, Tuzcu EM, Schoenhagen P, et al. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis. A randomized controlled trial. JAMA 2004; 291:1071–1080. 162. Cannon CP, Braunwald E, McCabe CH, et al. Comparison of intensive and moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004; 350:1495–1504. 163. LaRosa JC, Grundy SM, Waters DD, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Eng J Med 2005; 352:1425–1435. 164. Grundy SM, Cleeman JI, Merz CNB, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004; 110:227–239. 165. Sebastian JL, Tresch D. Anticoagulation therapy in the elderly. In, Fresch DD, Aronow WS, eds. Cardiovascular Disease in the Elderly Patient. New York: Marcel Dekker Inc., 1994: 213–261. 166. The Sixty Plus Reinfarction Study Research Group. A double-blind trial to assess long-term anticoagulation therapy in elderly patients after myocardial infarction: report of the Sixty Plus Reinfarction Study Research Group. Lancet 1980; 2:989–994. 167. Shepherd AMM, Hewick DS, Moreland TA, et al. Age as a determinant of sensitivity to warfarin. Br J Clin Pharmacol 1977; 4:315–320. 168. Hylek EM, Singer DE. Risk factors for intracranial hemorrhage in outpatients taking warfarin. Ann Intern Med 1994; 120:897–902. 169. Fraser AG. Pharmacokinetic interactions between alcohol and other drugs. Clin Pharmacokinet 1997; 33:79–90. 170. Beers MH, Ouslander JG, Rollingher I, et al. Explicit criteria for determining inappropriate medication use in nursing home residents. Arch Intern Med 1991; 151:1825–1832. 171. Beers MH, Ouslander JG, Fingold SF, et al. Inappropriate medication prescribing in skillednursing facilities. Ann Intern Med 1992; 117:684–689. 172. Beers MH, Fingold SF, Ouslander JG, et al. Characteristics and quality of prescribing by doctors practicing in nursing homes. J Am Geriatr Soc 1993; 41:802–807.

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173. Stuck AE, Beers MH, Steiner A, et al. Inappropriate medication use in community-residing older persons. Arch Intern Med 1994; 154:2195–2200. 174. Willcox SM, Himmelstein DU, Woolhandler S. Inappropriate drug prescribing for the community-dwelling elderly. JAMA 1994; 272:292–296. 175. Gurwitz JH. Suboptimal medication use in the elderly: the tip of the iceberg. JAMA 1994; 272:316–317. 176. Beers MH. Explicit criteria for determining potentially inappropriate medication use by the elderly: an update. Arch Intern Med 1997; 157:1531–1536. 177. Johnson JF. Considerations in Prescribing for the Older Patient. Scottsdale, NZ: PCS Health Systems (Eli Lilly), 1998:1/98. 178. Abrams WB. Cardiovascular drugs in the elderly. Chest 1990; 98:9809–9886. 179. Stein BE. Avoiding drug reactions: seven steps to writing safe prescriptions. Geriatrics 1994; 49:28–36. 180. Nagle BA, Erwin WG. Geriatrics. In DiPiro JT et al, eds. Pharmacotherapy. A Pathophysiologic Approach, 3rd ed. Stamford: Appleton and Lange, 1997: 87–100. 181. Hui KK. Gerontologic considerations in cardiovascular pharmacology and therapeutics. In: Singh BN, Dzau VJ, Vanhoutte PM, et al., eds. Cardiovascular Pharmacology and Therapeutics. New York, NY: Churchill-Livingstone, 1994:1130. 182. Appendices Cardiovascular Pharmacotherapeutics. 2nd ed. New York, NY: McGraw-Hill, 2003:1033–1036. 183. Aronow WS. Cardiovascular drug therapy in the elderly. In: Frishman WH, Sonnenblick EH, eds. Cardiovascular Pharmacotherapeutics. New York, NY: McGraw-Hill, 1997:1273. 184. Parker BM, Cusack BJ. Pharmacology and appropriate prescribing. In: Reuben DB, Yoshikawa TT, Besdine RW, eds. Geriatric Review Syllabus: A Core Curriculum in Geriatric Medicine. 3rd ed. Dubuque, IA: Kendall/Hunt Publishers, Am Geriatric Soc, 1996: 33. 185. Bressler R. Adverse drug reactions. In: Bressler R, Katz MD, eds. Geriatric Pharmacology. New York, NY: McGraw-Hill, 1993:54. 186. Frishman WH, Cheng A, Aronow WS: Cardiovascular drug therapy in the elderly. In: Tresch DD, Aronow WS: Cardiovascular Disease in the Elderly Patient. 2nd ed. New York, NY: Marcel Dekker, 1999:761. 187. Beers MH. Explicit criteria for determining potentially inappropriate medication use by the elderly: an update. Arch Intern Med 1997; 157:1531–1536.

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Systemic Hypertension in the Elderly William H. Frishman Department of Medicine, New York Medical College/Westchester Medical Center, Valhalla, New York, U.S.A.

INTRODUCTION There is strong evidence from large, well-controlled clinical trials which indicates that elderly patients with either combined systolic and diastolic hypertension or isolated systolic hypertension (ISH) benefit greatly from pharmacological blood pressure reduction (1). These studies demonstrate that treatment can reduce the risk of both cardiovascular and cerebrovascular morbidity. This chapter first reviews the pathophysiology of hypertension in the elderly and the rationale for both nonpharmacological and pharmacological treatments. HYPERTENSION IN THE ELDERLY Elderly hypertensive patients differ from young hypertensive patients in several respects. It is important to be aware of these differences when planning therapeutic interventions. The aging process is associated with multiple anatomical and physiological alterations in the cardiovascular system that can influence blood pressure regulation. Hypertension in young patients tends to be characterized by a hyperkinetic circulatory state, evidently resulting from increased sensitivity to circulating catecholamines (2). This state is expressed as an increase in heart rate, contractility, and cardiac output with no significant change in systemic vascular resistance. In contrast, systemic hypertension that is seen in elderly patients appears to be a consequence of structural vascular changes. A decreased vascular compliance and an increased resistance predominate and are associated with the narrowing of the vascular radius and increases in the vessel wall-to-lumen ratios (3). Histologically, the changes are apparent in the vascular subendothelial and media layers, which thicken with age and demonstrate increased connective tissue infiltration as well as calcification and lipid deposition (4). With age, this process results in a progressive increase in wall stiffness and tortuosity of the aorta and large arteries, often reflected by a rise in systolic pressure and a wide pulse pressure (5). The decreased vascular compliance seen in elderly patients may also result in reduced sensitivity of volume and baroreceptor function.

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Aging also affects the vascular endothelium, the cells of which become smaller and less uniformly aligned. This change may result in a decreased production of endogenous vasodilating substances (e.g., nitric oxide) and a decline in the local control of vascular tone (6,7). The aging process also alters the myocardium of elderly hypertensive patients. Although total heart size generally remains unchanged, mild to moderate left ventricular hypertrophy (LVH) often develops in response to an increased afterload. This hypertrophy tends to offset the decline in myocardial contractile speed and strength seen with aging (8). The elderly heart demonstrates microscopic foci of calcification and fibrosis as well as macroscopic calcification of the mitral and aortic valves and conduction system (9,10). Thus, the stiffened and hypertrophied left ventricle shows decreased diastolic filling and greater dependence on atrial contraction. Renal function also shows an age-dependent decline, which is further accelerated by chronically elevated blood pressure. The decline in renal function often manifests as a decline in glomerular filtration rate (11). Postglomerular increases in vascular resistance have been described as a possible compensatory mechanism and may further increase vascular pressure in the glomerulus (12). Despite the fact that elderly patients (including those with hypertension) tend to have lower plasma volumes than younger patients, their plasma renin levels are usually normal or low (13). Plasma levels of angiotensin-II, natriuretic peptides, and aldosterone are also decreased, and the response to antidiuretic hormone is blunted. In theory, these hormonal changes should help to lower or maintain arterial pressure in the elderly. Nonetheless, arterial blood pressure (usually systolic) appears to rise progressively with age (14–16). It has been estimated that 80% of elderly hypertensive patients present with concomitant medical conditions, which must be taken into consideration while planning therapeutic intervention (17). Examples include coronary artery disease, diastolic and systolic dysfunction, diabetes mellitus, hyperlipidemia, renal impairment, and chronic obstructive pulmonary disease. Elderly patients often take nonsteroidal anti-inflammatory drugs for arthritic conditions, which can cause an increase in blood pressure. Elderly patients also frequently suffer from LVH, insulin resistance, obesity, mental depression, and cognitive dysfunction. Therapy for hypertensive elderly patients needs to account for these and other concomitant diseases. RATIONALE FOR TREATMENT It has been estimated that 50–70% of elderly Americans have systemic hypertension, which is defined by the National Institutes of Health as blood pressure greater than 140/90 mmHg (1,18). Higher levels of either systolic or diastolic blood pressure are associated with an increased risk of cardiovascular morbidity or mortality that include cases of coronary artery disease, congestive heart failure, renal insufficiency, peripheral vascular disease, and stroke. Hypertension in the elderly poses an important problem for two reasons: (1) the proportion of elderly in the population is steadily increasing and (2) the incidence of hypertension—and therefore the risk of cardiovascular disease—increases with age (19). In the past, there was a tendency to de-emphasize the clinical significance of elevated blood pressure readings in the elderly and to downplay the need for therapeutic interventions. Increasing blood pressure was viewed as part of the normal aging process, and levels of blood pressure that would dictate treatment in young adults were often considered satisfactory or borderline in elderly patients. It was believed that

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the benefits of antihypertensive therapy might not be realized in patients with a limited life expectancy. It was also thought that elderly patients would be more susceptible to adverse drug reactions (e.g., orthostatic hypotension, cerebral hypoperfusion) (12,20). Several large, randomized, well-controlled trials were designed to investigate whether elderly hypertensives respond positively and receive benefits from pharmacological intervention (Table 1). Examples include the European Working Party Study on High Blood Pressure in the Elderly (EWPHE), the Swedish Trial in Old Patients with Hypertension (STOP), the Medical Research Council Trial on Treatment of Hypertension in Older Adults (MRC II), and the Systolic Hypertension in the Elderly Program (SHEP) (21–25). The combined data reported from these trials demonstrated a reduction in both cerebrovascular and cardiovascular morbidity and mortality in treatment groups. A metaanalysis by Holzgreve (19) describes a 40% reduction in stroke incidence and a 30% reduction in cardiovascular events with antihypertensive therapy. The SHEP study was particularly interesting because it investigated whether antihypertensive therapy can decrease cardiovascular risk in elderly patients with ISH (study entry criteria being systolic blood pressure 160–219 mmHg and diastolic pressure <90 mmHg), the most typical type of hypertension in the elderly (25). In the United States, the prevalence of diastolic hypertension tends to plateau around the age of 55, whereas the prevalence of systolic hypertension continues to rise, even after 80 years of age. Before the results of SHEP were published, many physicians held the belief that ISH in the elderly, reflecting an increase in rigidity of the arterial system, was only an index of an abnormal cardiovascular state and by itself did not play a direct role in the development of cardiovascular complications (26). This view persisted despite the compelling data from the Multiple Risk Factor Intervention Trial (MRFIT), which demonstrated that systolic blood pressure greater than 160 mmHg is a more significant risk factor, regardless of age, than diastolic pressure greater than 95 mmHg (27). The results of the SHEP trial showed conclusively that reduction or correction of hypertension strongly diminished the risk. Antihypertensive therapy was associated not only with a decrease in the number of cerebrovascular events but also with a 25% reduction in fatal and nonfatal coronary events and an even greater benefit in reducing episodes of congestive heart failure (Table 2). The greatest benefit of therapy was seen in patients with severe underlying disease. Even patients over 80 years benefit from treatment (28,29). However, hypertension might not be a risk factor for cardiovascular disease among very old hypertensive patients with advanced atherosclerosis (30). NONPHARMACOLOGICAL TREATMENT OF HYPERTENSION Lifestyle modifications in the elderly may be the only treatment modality necessary for preventing and managing milder forms of hypertension (31). Reduction in excess body weight and mental stress, modification of alcohol intake, and increased physical activity can also reduce the doses of antihypertensive drugs used for blood pressure control. In the Trial of Nonpharmacologic Intervention in the Elderly (TONE), it was shown that the combination of dietary sodium restriction and regular moderate physical activity (30–45 min of brisk walking on most days) can prevent hypertension in older subjects, and help to control blood pressure in known hypertensives (32). The Dietary Approaches to Stop Hypertension (DASH) trial showed that a diet rich in fruits and vegetables and low in saturated and total fat content can lower blood pressure without the need for additional drug treatment (33).

43

70–84

60

1627

4396

65–74

37

60–79

884

4736

30

60

840

39

31

Males (yr)

Age (yr)

Number of Patient-years

5.8

4.5

2.1

4.4

4.7

Duration (yr)

160–209

160–219

15/6

18/8

<115

9/6

10/10

16/11

Control

16/7

11/4

22/9

16/10

21/7

Treatment

BP Reductiona (mmHg)

<90

90–120

105

170

180–230

90–119

DBP range

160–239

SBP range

BP at entry (mmHg)

Differences between blood pressure in control and active treatment groups. Abbreviations: BP, blood pressure; SBP, systolic blood pressure; DBP, diastolic blood pressure; EWPHE, European Working Party Study on High Blood Pressure in the Elderly; STOP, Swedish Trial in Old Patients with Hypertension; SHEP, Systolic Hypertension in the Elderly Program; MRC, Medical Research Trial on Treatment of Hypertension in Older Adults. Source: From Ref. 19.

a

MRC Working Group

SHEP 1991

Randomized placebocontrolled doubleblind Randomized placebocontrolled single-blind Randomized placebocontrolled single-blind

Randomized placebocontrolled doubleblind Randomized non-blind

EWPHE 1985

Coppe and Warrender 1986 STOP 1991

Study Design

Study

Table 1 Characteristics of Some Long-Term Trials in Elderly Hypertensive Patients

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Table 2 Five-Year Absolute Benefits Found in Placebo-Controlled Endpoint Studies in ISH Number of events prevented/1000 patientsa

Stroke events Major CV events Deaths Dementia

SHEP (25)

Syst-Eur (64–66)

Syst-China (67)

33 55 — —

42 53 — 19

38 59 55 —

a

With the therapy/regimen used in this study. Abbreviations: ISH, isolated systolic hypertension; SHEP, Systolic Hypertension in the Elderly Program; Syst-Eur, Systolic Hypertension in Europe; Syst-China, Systolic Hypertension in China. Source: From Ref. 109.

Elderly patients with hypertension should be vigorously screened and treated for any additional cardiovascular risk factors that might be present, including cigarette smoking, hypercholesterolemia, diabetes mellitus, and excessive alcohol intake.

PHARMACOLOGICAL TREATMENT OF HYPERTENSION Diuretics Diuretics such as hydrocholorothiazide (HCTZ) and chlorthalidone have been the mainstay of antihypertensive drug treatment in the elderly for over 40 years. The Seventh Joint National Committee (JNC 7) report recommends diuretics as a medication of choice for initiating drug therapy of hypertension (1). Diuretic use will cause an initial reduction in intravascular volume, and will lower peripheral vascular resistance (34–36). These drugs will reduce an elevated blood pressure in over 50% of patients, and they are well tolerated and relatively inexpensive. Several clinical trials have assessed the efficacy of diuretics in hypertension and their ability to also reduce the complications of hypertension in the elderly, especially cardiovascular, cerebrovascular, and renal diseases. The EWPHE trial was a double-blinded, randomized, placebo-controlled study that evaluated 840 patients above 60 years of age with blood pressure ranging from 160 to 239 mmHg/90 to 119 mmHg (22). The subjects received, in an increasing stepwise fashion, HCTZ 25 to 50 mg and triamterene 50 to 100 mg to achieve blood pressure control or placebo. Methyldopa 500 mg was added if the blood pressure remained elevated. The subjects were followed for seven years and the outcomes of cardiovascular mortality and all-cause mortality were reported on. With active treatment, blood pressure was lowered by 19 mmHg/5 mmHg compared with placebo with less than 35% requiring the addition of methyldopa. It was found that 29 fewer cardiovascular events occurred per 1000 patient-years and 14 fewer deaths per 1000 patient-years, which was about a 38% decrease in total cardiovascular death compared with placebo. The National Heart Foundation of Australia studied 582 patients aged 60 to 69 years with diastolic blood pressures of 95 to 110 mmHg and started them on chlorothiazide 500 to 1000 mg to obtain blood pressure control or placebo (37). If blood pressure did not reach goal levels, a b blocker or methyldopa was added. Subsequently, hydralazine or clonidine was given, if necessary. Patients were followed for over five years, looking at the endpoints of fatal and nonfatal cardiovascular events. Seventy percent of the actively

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treated patients had diastolic blood pressure less than 90 mmHg, and of those actively treated, only 15% required more than two drugs. Most importantly, there was a decrease of 38% in total fatal and nonfatal cardiovascular events with active treatment compared with placebo. A third multicenter, randomized, double-blind, placebo-controlled trial, SHEP, looked at 4736 patients older than 60 years with systolic blood pressure 160 to 219 mmHg and diastolic pressures less than 90 mmHg (ISH) (25). Patients were started on placebo or chlorthalidone 12.5 mg, and the dose was doubled if the systolic blood pressure goal was not achieved. If at subsequent visits the blood pressure goal was not attained, then atenolol 25 to 50 mg was added. If atenolol was contraindicated, reserpine was given. After five years of treatment, the actively treated group had a reduced incidence of stroke, myocardial infarction (MI), and heart failure. Further analyses of the data show that the development of fatal and nonfatal heart failure was 55 of 2365 in the actively treated group compared with 105 of 2371 in the placebo group (38). Additionally, there were 583 non-insulin-dependent diabetics at baseline and their absolute risk reduction was twice as great in developing cardiovascular events (39). A randomized, single-blinded, placebo-controlled trial done by the MRC studied 4396 patients aged 65 to 74 years with a systolic blood pressure of 160 to 209 mmHg and a diastolic blood pressure less than 115 mmHg. The subjects received HCTZ 25 to 50 mg plus amiloride 2.5 to 5 mg, atenolol 50 to 100 mg, or placebo, and were followed for five years for incidence of stroke and coronary events as well as for all cardiovascular events (24). The results showed that both active treatments reduced blood pressure and the incidence of stroke equally, but the diuretic group experienced a more rapid and greater control of blood pressure compared with the b-blocker group, especially within the first three months of treatment, and the patients on the HCTZ regimen had 44% fewer coronary events and 29% fewer cardiovascular events than the atenolol treatment group. More recently, the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) studied 33,357 patients with a mean age of 67 who had stage I or II hypertension and at least one risk factor for coronary heart disease, and looked at fatal and nonfatal coronary heart disease or MI, stroke, and all coronary and cardiovascular events (40). Patients were randomized to receive chlorthalidone 12.5 to 25 mg, amlodipine 2.5 to 10 mg or lisinopril 10 to 40 mg, and followed for five years. If blood pressure goal was not achieved, step 2 drugs were added: atenolol 25 to 100 mg, reserpine 0.05 to 0.2 mg, clonidine 0.1 to 0.3 mg, twice a day. If necessary, step 3 treatment with hydralazine 25 to 100 mg, twice a day, was added. All treatment groups showed a similar decrease in the number of fatal and nonfatal coronary heart disease events. All treatments reduced blood pressure effectively, but the systolic blood pressure was lower in the diuretic group, and the lisinopril group had a 15% higher risk of stroke, a 10% higher risk of cardiovascular disease, and a 19% higher risk of heart failure compared with the chlorthalidone group. Furthermore, the amlodipine group had a 38% higher rate of heart failure when compared with the chlorthalidone group. Given the data from all these studies, it is reasonable to start antihypertensive therapy with diuretic agents in the elderly unless there are concomitant conditions present, such as angina pectoris or diabetes mellitus, which might warrant treatment with other agents. Why Not Use a Diuretic? As mentioned earlier, with aging, physiological changes occur that can be exacerbated with diuretic use. The elderly typically have contracted intravascular volumes and

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impaired baroreflexes, and diuretics cause sodium and water depletion (hypovolemia) and orthostatic hypotension. Older people have a high prevalence of LVH, which predisposes to ventricular ectopy and sudden death. Diuretics can cause hypokalemia and hypomagnesemia, which can increase ventricular ectopy and other arrhythmias. Typically, hypokalemia and hypomagnesemia can develop in the first few days of treatment. However, after that the body can achieve a new homeostatic balance and loss of these ions is lessened. Nevertheless, these agents are not advised in patients with baseline abnormalities, and when using them, potassium levels should be monitored and supplementation should be given as needed (41). Also, as we age, there is a lower renal blood flow and glomerular filtration rate. Diuretic use can cause a decrease in renal blood flow, creatinine clearance, and glomerular filtration rate. The elderly have a tendency toward hyperuricemia and glucose intolerance. Diuretics can cause increases in uric acid and glucose intolerance. Diuretic use can cause dyslipidemia. Cholesterol levels have been shown to increase in the first year of treatment with thiazides (42). However, their long-term use has been associated with an overall decrease in baseline cholesterol levels. Of the clinical trials mentioned, about 160 patients withdrew from the MRC trial because of side effects (less than the b-blocker group) and 15% withdrew from the ALLHAT trial because of side effects all comparable to the other treatment groups. In the SHEP trial, the most frequent event observed was abnormal electrolyte levels. Hypokalemia can be avoided when using an aldosterone antagonist diuretic such as spironolactone, triamterene, or eplerenone with a thiazide. Caution should be taken when using aldosterone inhibitors in patients with renal dysfunction. There may also be a greater blood pressure lowering effect with the combination than that seen with either diuretic drug used alone without the need for potassium supplementation. Eplerenone has been shown to reduce mortality in survivors of MI with evidence of left ventricular dysfunction (43). b-Adrenergic Blockers Although b blockers have been used for the treatment of hypertension in the elderly for several years, evidence of their benefit has not been convincing. The major studies of their efficacy, safety, and tolerability for the treatment of elderly hypertensives include the MRC, STOP, STOP-2, SHEP, and LIFE (Losartan Intervention for Endpoint Reduction in Hypertension Study) trials. The MRC trial assessed whether treatment with a diuretic or a b blocker in hypertensive older adults reduced the risk of stroke, coronary artery disease, and death (24). As described earlier, both treatments reduced blood pressure below the level of the placebo group, but only diuretic therapy showed a significant reduction in stroke, coronary events, and all cardiovascular events. The b-blocker group showed no significant reductions in these endpoints from placebo. Another significant finding of this trial was poor tolerability of b blockers, which is illustrated by the dropout rate of 63% of patients randomized to receive atenolol (24). The STOP trial was a multicenter, randomized, double-blind trial in subjects aged 70 to 84 years with systolic blood pressures ranging from 180 to 230 mmHg and/or diastolic blood pressure of 105 to 120 mmHg (23). Patients were initially treated with either a b blocker or a diuretic. However, two-thirds of the active subjects received combination therapy. The primary endpoints of stroke, MI, and cardiovascular death were reduced by active treatment compared with placebo. A separate report described no differences in monotherapy for diastolic blood pressure reduction during the first two months, but diuretics were more effective for systolic blood pressure reduction in

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the first two months of the trial (44). The b blockers included in the trial were 100 mg metoprolol controlled-release once daily, 50 mg atenolol once daily, or 5 mg pindolol once daily. At 12 months, the placebo-corrected changes in blood pressure were greatest when the b blocker was combined with a diuretic. There were no data collected in this trial to suggest either a benefit or a risk of b-blocker treatment in terms of mortality. STOP-2, a prospective, randomized, open-blinded endpoint design trial evaluated 6614 patients aged 70 to 84 years with systolic blood pressure greater than or equal to 180 mmHg and diastolic blood pressure greater than or equal to 105 mmHg, or both (45). Patients were assigned to receive either an angiotensin-converting enzyme (ACE) inhibitor, a calcium antagonist, or conventional drug therapy with a b blocker or a diuretic or a combination of both. There was no difference in the proportion of patients reaching a primary endpoint in this trial. Conventional therapy was just as effective as the newer agents in reducing cardiovascular events. Again, there were no findings in this trial to suggest either a benefit or risk from b-blocker treatment. As mentioned in the diuretics section of this chapter, the SHEP trial was a multicenter, randomized, double-blind, placebo-controlled trial of persons aged 60 years or older (25). Initial therapy was with 12.5 to 25 mg of chlorthalidone once daily. If blood pressure was not controlled, then 25 to 50 mg of atenolol or 0.05 mg of reserpine was added once daily. Forty-four percent of the subjects required combination drug therapy to achieve blood pressure control. This was a diuretic-based trial, and not a study of b blockers. A post hoc analysis suggested that neither the b blocker nor reserpine added to the benefits observed in this trial. The LIFE study was a double-blind, randomized, parallel group trial of 9193 participants aged 55 to 80 years, with essential hypertension and LVH ascertained by ECG (46). Participants were assigned to once-daily losartan-based or atenolol-based antihypertensive treatment for at least four years. Although both regimens effectively reduced blood pressure, losartan proved to be more effective than atenolol in preventing cardiovascular morbidity and mortality for a similar reduction in blood pressure. Losartan was also better tolerated, since more patients on b blockers withdrew because of the side effects of therapy. Messerli et al. published a meta-analysis of 10 studies comparing b blockers and diuretics for the treatment of hypertension in the elderly (47). A total of 16,154 patients aged 60 years and older were included. Two-thirds of the patients assigned to diuretics were well controlled on monotherapy. Diuretic therapy was superior to b blockade with regard to all clinical endpoints, and was more effective in preventing cerebrovascular events, fatal stroke, coronary artery disease, cardiovascular mortality, and all-cause mortality. Therefore, the clinical benefits of b blockers as monotherapy in the treatment of systemic hypertension in the elderly are poorly documented, although they may have a role in combination therapy, especially with diuretics. b Blockers have an established role in the treatment of certain arrhythmias, migraine headaches, senile tremor, coronary artery disease, and congestive heart failure. Consideration should be given to adding b blockers as a treatment regimen in hypertensive patients with any of these comorbid conditions (48–52). It was shown that in older patients with ISH, a clinical heart rate greater than 79 bpm was a significant predictor for an increase in all-cause, cardiovascular, and noncardiovascular mortality, suggesting a role for b blockers and rate-lowering calcium blockers in this population (53). b Blockers, especially nonselective b blockers, should be used carefully in patients with asthma and chronic obstructive pulmonary disease, since they can induce bronchospasm by inhibiting sympathetic signaling at the b2-adrenergic receptors (48).

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As glucose metabolism is modulated by the sympathetic nervous system, b blockers can exacerbate diabetes mellitus by inhibiting this pathway. Although a deterioration in glucose tolerance has been associated with nonselective agents such as propranolol, this finding has not been as frequently observed with b1-selective agents such as metoprolol and atenolol (48). Also, b blockers can mask the sympathetic manifestations of hypoglycemia. These probably do not increase the risk of depression, but they can cause erectile dysfunction (48). Viagra1 can be used with concomitant antihypertensive drugs to alleviate erectile dysfunction. Calcium Blockers The calcium channel blockers are a heterogeneous group of drugs with widely variable effects on heart muscle, sinus node function, atrioventricular conduction, peripheral blood vessels, and coronary circulation (54–57). From a chemical standpoint, they can be divided into three main groups: phenylalkylamines (verapamil), benzothiazepines (diltiazem), and dihydropyridines (nifedipine, nicardipine, nimodipine, amlodipine, felodipine, isradipine). Despite their heterogeneity, they all block the influx of calcium ions into the cells of vascular smooth muscle and myocardial tissue (58). The observation that calcium antagonists are significantly more effective in inhibiting contraction in coronary and peripheral arterial smooth muscle than in cardiac and skeletal muscle is of great clinical importance. This differential effect is explained by the observation that arterial smooth muscle is more dependent on external calcium entry for contraction, whereas cardiac and skeletal muscle rely on a recirculating internal pool of calcium (59). Because calcium antagonists are membrane-active drugs, they reduce the entry of calcium into cells and, therefore, exert a much greater effect on vascular wall contraction. This preferential effect allows calcium antagonists to dilate coronary and peripheral arteries in doses that do not severely affect myocardial contractility or have little, if any, effect on skeletal muscle (54). Based on the above mechanisms of action, the calcium antagonists appear well suited for use in elderly patients whose hypertensive profile is based on increasing arterial stiffness, decreased vascular compliance, and diastolic dysfunction secondary to atrial and ventricular stiffness (60). Because they have multiple clinical applications, including treatment of angina pectoris and management of supraventricular arrhythmias, calcium antagonists also hold promise in the treatment of elderly hypertensive patients with comorbid cardiovascular conditions. In general, calcium antagonists appear to be well tolerated by the elderly. Most adverse effects of the dihydropyridines are attributable to vasodilation; examples include headaches and postural hypotension. Postural hypotension is associated with an increased risk of dizziness and falls; thus, it is a serious concern for elderly patients. Peripheral edema may also result and be confused with symptomatic congestive heart failure (61). Verapamil, which may be particularly useful in elderly patients with diastolic dysfunction of the left ventricle, has been noted to increase constipation (62). Verapamil and diltiazem can precipitate heart blocks in elderly patients with underlying conduction defects. Agerelated declines in renal or hepatic function alter drug disposition in elderly patients, mostly as a result of declines in first-pass metabolism. This decline decreases total body clearance and increases elimination half-life. Individualized dose adjustments or dosing schedules help to decrease adverse effects (63). The published results of large double-blind, randomized, placebo- and activecontrolled trials have demonstrated the safety and efficacy of calcium antagonists in elderly patients with both ISH and combined systolic and diastolic hypertension (Table 3).

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Table 3 Trials of Antihypertensive Therapy with Calcium Antagonists in Elderly Patients Trial Duration Number of patients

Entry criteria

Therapy

Endpoints

ALLHAT 5 yr 40,000

Age >55 yr BP: 140/90 or lower if treated Other

1st: fatal/nonfatal MI 2nd: morbidity, mortality, cost, benefits of cholesterol reduction

CONVINCE 5 yr 15,000

Age 55 yrs BP: systolic 140–190 or diastolic 90–100 or 175–100 if treated Other Age 50–80 yr BP: diastolic 100–115

1st: amlodipine, lisinopril, doxazosin, or chlorthalidone + pravastatin 2nd: reserpine, clonidine, atenolol, or hydralazine at physician’s discretion 1st: verapamil, atenolol, or HCTZ 2nd: HCTZ or b blocker for achievement of BP goal 3rd: moexipril

HOT 2.5 yr 18,000

INSIGHT 3 yr 6321 NORDIL 5 yr 10,881

Age 55–80 yr BP  150/95 (sitting) or systolic > 160 Other Age 50–74 yr BP: diastolic >110 or >100 (sitting) if treated or other risk factors present

PREDICT 4–4.5 yr 8000–8500

Age 55 yr BP: 90–109/140–179 Other

SISH 2 yr 171

Age >55 yr BP: systolic 140–159

STOP-2 4 yr 6600

Age 70–84 yr BP>180/105 (sitting)

1st: felodipine + aspirin or placebo 2nd: captopril, enalapril, ramipril, atenolol, metoprolol, or propranolol, as needed 1st: long-acting nifedipine or HCTZ-amiloride 2nd: atenolol or enalapril 1st: diltiazem, diuretic, or beta blocker 2nd: ACE inhibitor, b blocker, or diuretic 3rd: ACE inhibitor, b blocker, or diuretic

1st: diltiazem or chlorthalidone 2nd: open-label therapy 3rd: open-label therapy 1st: felodipine or placebo

1st: felodipine, isradipine, atenolol, metoprolol, pindolol, enalapril, lisinopril, or HCTZamiloride

1st: fatal/nonfatal MI, stroke; sudden cardiac death 2nd: cardiovascular disease, number and time of deaths 1st: fatal/nonfatal MI, stroke; achievement of BP goal 2nd: benefits of aspirin

1st: fatal/nonfatal MI, stroke; congestive heart failure 2nd: mortality 1st: fatal/nonfatal MI, stroke; sudden cardiac death 2nd: mortality, ischemia heart disease or attack, atrial fibrillation, congestive heart failure, renal disease 1st: fatal/nonfatal cardiovascular disease

1st: compare effects on EKG measurements of ventricular wall thickness and ventricular function 1st: fatal/nonfatal MI, stroke; sudden cardiac arrest 2nd: cardiovascular disease, cost, institutionalization, tolerability of therapy

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Table 3 Trials of Antihypertensive Therapy with Calcium Antagonists in Elderly Patients (Continued ) Trial Duration Number of patients Syst-Eur 5 yr 3000 Syst-China

Entry criteria

Therapy

Endpoints

Age  60 yr BP: systolic 160–219 or diastolic < 95 (sitting) Same as Syst-Eur

1st: nitrendipine or placebo 2nd: enalapril, HCTZ

1st: fatal/nonfatal stroke 2nd: MI, congestive failure

1st: nitrendipine or placebo 2nd: captopril, HCTZ, or placebo

1st & 2nd same as Syst-Eur

Abbreviations: BP, blood pressure (mmHg); MI, myocardial infarction; EKG, electrocardiographic; HCTZ, hydrochlorothiazide; ACE, angiotensin-converting enzyme; ALLHAT, Antihypertensive and Lipid-lowering Treatment to Prevent Heart Attack Trial; CONVINCE, Controlled Onset Verapamil Investigation of Cardiovascular Endpoints; HOT, Hypertension Optimal Treatment Study; INSIGHT, International Nifedipine Study: Intervention as a Goal in Hypertension Treatment; NORDIL, Norwegian Diltiazem Intervention Study; PREDICT, Prospective Randomized Evaluation of Diltiazem CD Trial; S1SH, Stage 1 Systolic Hypertension; STOP-2, Swedish Trial in Old Patients with Hypertension 2; Syst-Eur, Systolic Hypertension in Europeans Study; Syst-China, Systolic Hypertension in China. Source: From Ref. 110.

Three studies have evaluated two dihydropyridines, long-acting nitrendipine, and felodipine in patients with ISH. The Systolic Hypertension in Europe (SYST-EUR) study was limited to patients aged 60 years and older with a resting systolic pressure of 160 to 219 mmHg, and a diastolic pressure less than 95 mmHg. Patients were randomized to receive nitrendipine or placebo. If additional blood pressure control was necessary, patients received an ACE inhibitor and then a diuretic. Compared with placebo, nitrendipine therapy was associated with significant reductions in the rate of stroke, major cardiovascular events, and cognitive disorders (64–66). On the basis of this study, the JNC-7 guidelines include the use of dihydropyridine calcium antagonists in addition to thiazide diuretics as first-line treatment for ISH in the elderly (1). The Systolic Hypertension in China (SYST-CHINA) study also looked at nitrendipine as a first-line treatment modality compared with placebo in elderly patients with ISH (67). Compared with placebo, nitrendipine was associated with a reduction in stroke events, major cardiovascular events, and mortality. The stage I Systolic Hypertension in the Elderly (68) was a pilot trial that enrolled elderly patients (>55 years of age) with mild (stage 1) systolic hypertension (140 to 155 mmHg), a population not studied in SHEP, SYST-EUR, and SYST-CHINA. Felodipine was compared with placebo in an attempt to reduce systolic blood pressure by 10%. Felodipine was shown to be more effective than placebo in reducing blood pressure. In addition, the drug was shown to reduce ventricular wall thickness and improved ventricular function (68,69). A number of studies have been completed comparing various calcium blockers to other antihypertensive drugs in older subjects with combined systolic and diastolic hypertension (Table 3). STOP-2 enrolled 6600 patients, ranging in age from 70 to 84 years with a supine blood pressure of 180/105 mmHg or higher (45). The original STOP

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trial (23) compared the effects of diuretics and b blockers in elderly hypertensives in terms of cardiovascular morbidity and mortality. STOP-2 (45) compared these two treatments with a calcium blocker (felodipine or isradipine) or an ACE inhibitor (enalapril or lisinopril). There was no difference between the three treatment groups with respect to the combined endpoints of fatal stroke, fatal MI, and other cardiovascular diseases (45,70). There was a lower incidence of nonfatal MI and congestive heart failure in the ACE inhibition group compared with the other treatment modalities. In the International Nifedipine Study Intervention as a Goal in Hypertension Treatment (INSIGHT) (71), 6321 elderly patients aged 55 to 80 years were randomized to double-blind treatment with either long-acting nifedipine gastrointestinal therapeutic system (GITS) or the combination drug coamilozide (HCTZ and amiloride). The study endpoints were overall cardiovascular morbidity and mortality, and both treatments appeared equally effective in preventing vascular events. In the Nordic Diltiazem Study (NORDIL) (72), 10,881 patients aged 50 to 74 years with systemic hypertension were randomized to receive firstline therapy with diltiazem, diuretics, or b blockers. Diltiazem was as effective as the other treatments in reducing the incidence of combined study endpoints of stroke, MI, and other cardiovascular deaths. In the Prospective Randomized Evaluation of Diltiazem CD Trial (PREDICT) study, 8000 patients aged 55 years and older were randomized to receive either diltiazem or chlorthalidone. The results have not been published to date. Other studies have demonstrated the efficacy of calcium-channel blockers used alone or in combination in elderly patients when compared to alternative medications (73–77). The Hypertension Optimal Treatment (HOT) trial studied 18,000 patients aged 50 to 80 years. The study examined whether maximal reduction of diastolic blood pressure with antihypertensive drugs and aspirin could cause a further reduction in cardiovascular events (MI or stroke) or be associated with harm (J-curve hypothesis) (78). Felodipine, a long-acting dihydropyridine, was used as the first-line treatment for all patients and aspirin (75 mg) or placebo was also given. An ACE inhibitor, a b blocker, and a thiazide diuretic could be given to achieve the desired diastolic blood pressure goal. The study results showed that maximal protection with antihypertensive therapy was seen when a diastolic blood pressure of 82.6 mmHg was achieved; in diabetic patients, an additional reduction in diastolic blood pressure (below 80 mmHg) was needed to achieve maximal benefit. A J-curve response was not observed despite major reductions in blood pressure. The HOT study had greater success in achieving blood pressure targets among the oldest subjects with a low incidence of medication side effects. The Controlled-Onset Verapamil Investigation of Cardiovascular Events trial (CONVINCE) (79) (Table 3) was designed to compare a delayed slow-release verapamil delivery system with atenolol or HCTZ in 15,000 hypertensive patients aged 55 years and older. The sponsor stopped the study for financial reasons, and the accumulated data from the trial showed no difference in the clinical endpoints with either treatment regimen. Calcium antagonists are well suited for treating elderly hypertensive patients who often have concomitant diseases, especially coronary artery disease or heart failure due to diastolic dysfunction (Table 4). In an elderly patient with both hypertension and ischemic heart disease (with or without angina pectoris), calcium antagonists are an appropriate therapy for both conditions (80). The combination of a calcium antagonist and a b blocker is well tolerated and serves to offset transient increases in the neurohumoral reflex (81). A combination regimen of felodipine and metoprolol has been evaluated, but this formulation is not yet available for clinical use in the United States (82). Combinations of calcium blockers with ACE inhibitors have also been evaluated (83). The edema seen with the calcium blocker is reduced, while there is greater blood pressure efficacy with

14.7 11.1 2.0 3.5 22.9 — —

Angina MI CHF Stroke Diabetes Dementia Depression

8.6 4.4 1.3 1.3 20.1 — —

Women 4.9 — — 1.4 10.1 0.4 11.1

SHEP 8.8 3.5 — 1.2 10.5 0.8 —

Syst-Eur

— 1.4 4.0 — —

Angina and/or MI: 9.4

Syst-China

Trial participants (%) (age > 60 yr)

12.1 11.9 3.0 9.5 20.0 — —

Men 16.0 4.6 4.9 4.9 15.2 — —

Women

Elderly Patients with hypertension (%) (age > 65 yr)

16 40 36 23 —

Angina and/or MI: 20

Residents of nursing homes (%) (age 65–74 yr)

Abbreviations: MI, myocardial infarction; CHF, congestive heart failure; SHEP, Systolic Hypertension in the Elderly Program; Syst-Eur, Systolic Hypertension in Europe; Syst-China, Systolic Hypertension in the Elderly Chinese; — , data not available. Source: From Ref. 111.

Men

Cardiovascular disease

General population (%)

Table 4 Incidence of Comorbid Conditions Observed in the General Elderly Population, Hypertension Trial Participants, Elderly Patients with Hypertension, and Nursing Home Residents with Hypertension

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combination therapy than with monotherapy. Recently a combination of amlodipine and valsartan was approved for clinical use in hypertension. Elderly patients with diastolic dysfunction have impaired myocardial relaxation, which leads to decreased ventricular filling. Impairment may be related to age or to myocardial ischemia from coronary disease (84). Calcium antagonists may help to improve left ventricular diastolic function in such patients (85). ACE Inhibitors ACE inhibitors block the conversion of angiotensin-I to angiotensin-II both systemically and locally in arterioles to lower total peripheral vascular resistance. Blood pressure is reduced without reflex stimulation of heart rate and cardiac output. With age, angiotensin levels become lower and, theoretically, ACE inhibitors should not be as effective as other therapies. However, multiple studies have shown otherwise. The Captopril Prevention Project (CAPPP) compared captopril with a b blocker in 10,925 older patients with diastolic blood pressure greater than 100 mmHg (86). Patients receiving captopril had a lower rate of cardiovascular death; patients on b blockers had a lower stroke rate. Other studies mentioned earlier (ALLHAT and STOP-2) (40,45) showed that ACE inhibitors can reduce the risk of stroke and coronary heart disease as well as other antihypertensive drugs, although in ALLHAT there was less of a reduction, especially in Black patients. ACE inhibitors have been shown to reduce the risk of recurrent stroke when combined with a diuretic in patients who have already had a stroke or transient ischemic attack (87). In addition, they have been shown to reduce mortality in patients with heart failure and poor left ventricular function (88–92). The drugs appear to reduce the progression of renal disease in type 1 diabetic patients with proteinuria (93). The Heart Outcomes Prevention Evaluation (HOPE) trial evaluated the effects of ramipril in 9297 patients over the age of 55 who were both normotensive and hypertensive in a placebo-controlled trial (94). Subjects had a previous history of stroke, coronary disease, peripheral vascular disease, and diabetes mellitus without heart failure. After five years, the endpoints of MI, stroke, or cardiovascular death were evaluated. Ramipril was associated with a lower blood pressure than placebo, and reduced the risk of the combined primary outcome by 25%, MI by 22%, stroke by 33%, and cardiovascular death by 37%. Given all the available data, ACE inhibitors should be considered as drugs of choice in elderly hypertensive patients with heart failure and/or diabetes mellitus. The main adverse effects of ACE inhibitors include excessive hypotension, chronic dry cough, and, rarely, angioedema or rash. Renal failure can develop in those with renal artery stenosis. Hyperkalemia can occur in patients with renal insufficiency or those taking potassium supplements. Therefore, these agents must be used carefully in patients with renal impairment. Rarely, neutropenia or agranulocytosis can occur; therefore, close monitoring is suggested in the first few months of therapy.

Angiotensin Receptor Blockers The angiotensin receptor blockers (ARBs) are a relatively new class of drugs employed in the treatment of hypertension. These agents work selectively at the AT1-receptor subtype, the receptor that mediates all the known physiological effects of angiotensin-II that are believed to be relevant to cardiovascular and cardiorenal homeostasis.

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A large-scale open-label clinical experience trial ACTION study showed the effectiveness of the ARB candesartan cilexetil alone or in combination with other agents in 6465 patients with a mean age of 58 who had either combined or ISH (95). The LIFE study compared losartan with atenolol in 9193 patients aged 55 to 80 years with essential hypertension and LVH (46). The study showed a substantially reduced rate of stroke in the losartan-treated group despite comparably reduced blood pressure reduction in both the losartan and atenolol treatment groups. A primary composite outcome of death, stroke, and cardiovascular mortality showed a significant benefit in favor of losartan. There was also a greater effect on LVH regression with losartan compared with atenolol. Overall, safety and efficacy trials have shown that ARBs are similar to other agents in reducing blood pressure and are well tolerated. ARBs have also been found useful in protecting the kidney in the setting of type 2 diabetes (46), both in patients with established diabetic nephropathy with proteinuria and in patients with microalbuminuria (93). In addition, the drugs have been shown useful in reducing mortality and morbidity in patients with congestive heart failure (93,96), used alone and in combination with an ACE inhibitor (97). In elderly patients, ARBs can be considered a first-line treatment in hypertensive patients with type 2 diabetes, and as an alternative to ACE inhibitors in hypertensive patients with heart failure who cannot tolerate ACE inhibition (96). In a study of patients with chronic heart failure and preserved left ventricular ejection fraction (>40%), candesartan was shown to reduce the number of hospital admissions for heart failure compared with placebo, but the active treatment had no impact on mortality (98). a-Adrenergic Blocking Agents In large comparative clinical trials, the efficacy and safety of a blockers have been well documented (48). Doxazosin 2 to 8 mg daily was one of the drugs used in the ALLHAT trial, and that arm of the study was discontinued after an interim analysis showed a 25% greater rate of cardiovascular events compared with chlorthalidone, largely driven by congestive heart failure (99). On the basis of this study, a blockers should not be considered as first-line monotherapy treatment for hypertension, but as part of a combination regimen to provide maximal blood pressure control. These drugs are a treatment of choice for symptomatic prostate hypertrophy, and caution should always be used because of their potent hypotensive actions. Direct Renin Inhibitors Recently released for clinical use, aliskiren is the first orally active direct renin inhibitor approved for the treatment of systemic hypertension. In doses of 150 to 300 mg taken once daily, aliskiren can effectively lower blood pressure, and it was shown to be as effective as ARBs and ACE inhibitors for blood pressure management (100–102). Combining aliskiren with HCTZ, ramipril, or amlodipine causes greater blood pressure– lowering than with either agent used alone (100,103). There is no experience with combination of aliskiren and b-blocker therapy, or with maximal dose ACE inhibitors. There are also little data available in Black hypertensive patients (104). Aliskiren has been studied in older patients (>75 years) and appears to be well tolerated with no dose adjustment necessary. In addition, there is no dose adjustment of aliskiren necessary in older patients with renal disease. The major dose-related side effect

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Table 5 Rationale for Combination Drug Therapy for Hypertension Increased antihypertensive efficacy Additive effects Synergistic effects Reduced adverse events Low-dose strategy Drugs with offsetting actions Enhanced convenience and compliance Prolonged duration of action Potential for additive target organ protection Source: From Ref. 106.

of aliskiren is a lower incidence of mild diarrhea, which in clinical studies did not lead to treatment discontinuation (105). Centrally Acting Agents Centrally acting agents (e.g., clonidine) are not first-line treatments in the elderly because many patients experience troublesome sedation. They can be used as part of a combination regimen to maximize blood pressure control. Combination Therapy Treating hypertension with combination therapy provides more opportunity for creative solutions to a number of problems. Five issues in combined therapy—some practical, some speculative—are listed in Table 5 (106). The most obvious benefit of drug combinations is the enhanced efficacy that fosters their continued widespread use. Theoretically, some drug combinations might produce synergistic effects that are greater than would be predicted by summing the efficacies of the component drugs. More commonly, combination therapy achieves a little less than the sum of its component drug efficacies. In contrast, some combinations of drugs produce offsetting interactions that weaken rather than strengthen their antihypertensive effects, as previously seen with agents affecting peripheral-neuronal actions. For instance, guanethidine and reserpine produced this offsetting interaction; but since these agents are now used only rarely, this issue need not be considered further. A second benefit of combination therapy concerns the avoidance of adverse effects. When patients are treated with two drugs, each drug can be administered in a lower dose that does not produce unwanted side effects but still contributes to overall efficacy. A third issue concerns convenience. Obviously, the multiple drugs of a combination regimen could be confusing and distracting to elderly patients, and could lead to poor treatment compliance. On the other hand, a well-designed combination pill that incorporates logical doses of two agents could enhance convenience and improve compliance. Further potential value of combination treatment may result from the effects that two drugs have on each other’s pharmacokinetics. Although this has not been studied well, there might be situations where the clinical duration of action of the participating drugs becomes longer when used in combination than when they are administered as monotherapies. Finally, it is interesting to consider the attributes of such agents as ACE inhibitors, ARBs, and calcium channel blockers, which exhibit antigrowth or antiatherosclerotic actions in addition to their blood pressure–lowering properties. Is it

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Table 6 Approach to Blood Pressure Reduction in the Elderly I. II.

Modify lifestyle (exercise, diet) Initiate drug treatment with thiazide diuretic in uncomplicated hypertension (combined systolic/diastolic) and isolated systolic hypertension. III. Initiate alternative therapy in hypertensive patients with angina pectoris (b blockers, calcium blockers), heart failure (ACE inhibitors or ARBs), type 1 diabetes (ACE inhibitors), type 2 diabetes (ARBs). IV. Use low-dose combination regimens to maximize blood pressure control when goals are not met; thiazides should be part of combination regimen. Abbreviations: ACE, angiotensin-converting enzyme; ARBs, angiotensin receptor blockers

possible that combinations of these newer agents may provide even more powerful protective effects on the circulation? CONCLUSION A meta-analysis of nine trials with more than 15,000 elderly subjects reported that allcause mortality, stroke mortality, and coronary mortality were reduced by lowering blood pressure (107). Elderly patients with hypertension, especially ISH, are the demographic group most likely to have uncontrolled hypertension. Despite clear evidence in elderly patients that morbidity can be reduced with antihypertensive drugs, clinicians are less aggressive with pharmacotherapy than they could be. The elderly also have concomitant diseases that often warrant major reductions in systolic blood pressure. Decreasing blood pressure in these age groups may be difficult. It has to be done carefully and although all of the guidelines suggest that the goal of systolic blood pressure should be less than 140 mg, this is not achievable in all patients. Blood pressure should also be lowered in patients with a previous stroke or transient ischemic attack (87). Diuretics should probably be considered the first-line treatment for hypertension in the elderly unless other conditions exist (angina pectoris, diabetes mellitus, congestive heart failure), which may warrant treatment with other antihypertensive drugs (Table 6). With the stricter blood pressure goals, most patients will require combination antihypertensive regimens, especially for control of systolic blood pressure elevations (108). REFERENCES 1. Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC-VII). JAMA 2003; 289:2560–2572. 2. Folkow B. The pathophysiology of hypertension. Differences between young and elderly patients. Drugs 1993; 46(suppl 2):3–7. 3. Folkow B. Sympathetic nervous control of blood pressure. Role in primary hypertension. Am J Hypertens 1989; 2:103S–111S. 4. Korner PL, Bobik A, Angus JA, et al. Resistance control in hypertension. J Hypertens 1989; 7(suppl 4):S125–S134. 5. Yin FCP. The aging vasculature and its effects on the heart. In: Weisfeldt ML, ed. The Aging Heart. New York: Raven Press, 1980:137–214. 6. Wei JY. Use of calcium entry blockers in elderly patients. Special considerations. Circulation 1989; 80(suppl 4):171–177.

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Disorders of Lipid Metabolism Joseph E. Thomas and JoAnne M. Foody Yale University School of Medicine, New Haven, Connecticut, U.S.A.

INTRODUCTION The majority of coronary heart disease (CHD) mortality and morbidity occurs in individuals over 65 years of age (1) and cardiovascular disease accounts for nearly 70% of all deaths in this age group. Older patients have a particularly poor prognosis, and they are more likely to suffer disability following a cardiovascular event. In addition, older persons are more susceptible to stroke, which accounts for 1 in 15 deaths in the United States and is the leading cause of serious, long-term disability. The majority of strokes, 80%, occur in people over the age of 65 years. Finally, heart failure is of epidemic proportions in older persons and new data suggest that lipid lowering may provide benefit in these patients (1). Given increasing life expectancy and population aging, the number of individuals at risk of cardiovascular events, including CHD, heart failure, and stroke, is expected to increase. However, many older patients do not currently have their cardiovascular risk factors assessed or suitably controlled. While national and international guidelines consider age to be a risk factor for CHD (2), older persons are paradoxically less likely to receive aggressive primary and secondary prevention (3,4). The aim of this chapter is to review recent clinical trial data regarding lipid lowering in older individuals and to discuss current gaps in the treatment of older persons. HYPERCHOLESTEROLEMIA AS A PREDICTOR OF CARDIOVASCULAR RISK Hypercholesterolemia in older patients is a potentially important modifiable risk factor for cardiovascular events. It is highly prevalent and is associated with adverse clinical outcomes in younger subjects. Yet, the clinical significance of hyperlipidemia in the elderly has been the subject of much debate. While it is generally held that the relationship between CHD and cholesterol is continuous and graded, the results of several studies suggest that the strength of this relationship decreases markedly in patients over the age of 75. For example, some studies have indicated that the predictive value of cholesterol declines in patients older than 70 years (5,6), and have challenged whether cholesterol is relevant in older individuals (7). In contrast, several epidemiological

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investigations of CHD have reported that risk factors in the middle-aged, including cholesterol, remain relevant than in older persons (8,9). Thus, the role of hyperlipidemia in older persons remains controversial. In a cohort of men and women from the Established Populations for the Epidemiologic Studies of the Elderly, with mean ages of 78 and 79 years, respectively, Krumholz et al. found that the prevalence of total cholesterol levels greater than 240 mg/dL was 34% for women and 16% for men (5). There was no significant association between the total cholesterol level and the incidence of myocardial infarction (MI), unstable angina, CHD mortality, or all-cause mortality. In fact, the highest rates of MI were in the lowest cholesterol group. In women, survival was lowest in those with total cholesterol less than 200 mg/dL, while patients with total cholesterol greater than 240 mg/dL had the highest survival rate. In an age-specific analysis of the Framingham Heart Study, Kronmal demonstrated that as age increased, the relative risk associated with a high cholesterol level decreased (10). In this study, total cholesterol values peaked at about age 50 for men and at age 60 for women. Total cholesterol levels were higher in women of all ages. Low-density lipoprotein (LDL) cholesterol levels followed a similar age and gender pattern. The positive relationship between total serum cholesterol and all-cause mortality disappeared by age 60, and a significant negative relationship was evident at age 80. For an 80-year-old man with cholesterol greater than 240 mg/dL, five-year survival was 73%; if the cholesterol was less than 240 mg/dL, five-year survival declined to 49%. Corresponding five-year survival rates for women with cholesterol levels above or below 240 mg/dL were 74% and 70%, respectively. These relationships were not explained by coexisting illnesses. For CHD mortality, the relationship with total cholesterol remained positive, but the magnitude declined with age. While these studies failed to detect a continuous relationship between cholesterol and CHD in the elderly, other prospective studies have reported significant, positive correlations between both total cholesterol and LDL cholesterol and CHD mortality and events in older patients. In white males aged 60 to 79 years enrolled in the Kaiser Permanente Coronary Heart Disease in the Elderly Study, Rubin et al. evaluated the CHD risk associated with high blood cholesterol (11). Independent of age, mortality from CHD rose with cholesterol levels. In male participants aged 65 to 74 years enrolled in the Honolulu Heart Program, CHD rates increased progressively with each quartile of cholesterol level (12). Total cholesterol was shown to be an independent predictor of CHD risk and this effect was not diminished with increasing age. In a cohort of elderly men and women in a long-term health care facility, mean age 82 years, Aronow et al. examined predictors of new coronary events. In this analysis, total cholesterol levels over 200 mg/dL in men and over 250 mg/dL in women were associated with an increase in coronary events (13). In a study of men and women aged 64 to 87 years in the Netherlands, total cholesterol was significantly associated with CHD mortality in women only. The Bronx Aging Study found that low high-density lipoprotein (HDL) cholesterol levels were a powerful predictor of CHD in elderly men, while high LDL cholesterol was a predictor of MI in elderly women (14). In a review of 22 cohort studies, Manolio et al. found that total cholesterol and LDL cholesterol levels were significantly correlated with fatal CHD in both men and women across a broad range of populations including patients older than 65 years (15). While both the relative risk and the consistency of the relationship decreased with increasing age, these data suggest that high serum cholesterol confers an increased risk of CHD in patients up to 75 years of age. After age 75, the relative risk may drop off substantially, and few data exist to assess the effect of cholesterol on CHD risk in the very old (i.e.,
85 years).

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In a subgroup analysis of the Systolic Hypertension in the Elderly Program (SHEP), Frost et al. reported on the relationship between serum lipids and CHD in an elderly population with a mean age of 72 years. Multivariate analysis revealed that levels of total, non-HDL and LDL cholesterol were significantly related to CHD incidence during more than four years of follow-up. Specifically, a 40 mg/dL increase in total or LDL cholesterol was associated with a 30–35% increase in CHD events in this population (16). There are several plausible explanations for discrepancies across studies in the relationship between cholesterol and outcomes in the elderly. Prevalent comorbidity and vulnerability to competing risks from other illnesses may confound the effects of cholesterol on CHD events (17). Cholesterol may have the strongest association with cardiovascular events in elderly patients at greatest risk, such as those with prior MI, but the association may be weak or nonexistent among patients in low risk subgroups. Few studies have included information on HDL or LDL lipoprotein cholesterol or on triglycerides, which would allow for a more refined assessment of risk. As noted earlier, it is especially relevant to examine the effect of risk factors on absolute risk in older patients. Since the number of coronary events increases with age, the risk of CHD events attributable to elevated cholesterol actually increases as individuals age, despite the fact that relative risk may decline. Viewed in this way, cholesterol is more, not less, important as a predictor of cardiovascular events in the elderly (11). Epidemiological studies of the relation of lipoprotein levels to atherosclerosis in the elderly have concentrated primarily on coronary disease event rates, with little information concerning the impact of cholesterol on stroke rates. Until recently, cholesterol levels were not considered to be related to incident stroke in either younger or older individuals. With the advent of new imaging techniques that distinguish between hemorrhagic and atherothrombotic strokes, it has become clear that cholesterol levels are directly related to the incidence of atherothrombotic stroke, but inversely related to the incidence of hemorrhagic stroke (18). In Western societies, where most strokes are related to atherothrombosis, this observation may have particular significance for older patients.

CHOLESTEROL INTERVENTION AND CARDIOVASCULAR DISEASE PREVENTION Relatively few studies have examined the impact of age on the efficacy of statins and other lipid-lowering drugs. However, a growing number of observational studies and randomized clinical trials with sufficiently large numbers of older persons indicate that statin therapy is equally efficacious in older and younger persons at high risk for cardiovascular events. Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) reduce cardiovascular risk in a wide range of patients, and guidelines from both the American Heart Association/American College of Cardiology and the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) recommend statins as first-line therapy for the management of dyslipidemia, irrespective of patient age. As discussed below, not only are data emerging to support aggressive lipid lowering for the reduction of CHD events, but new data demonstrate the importance of lipid lowering in reducing cerebrovascular and peripheral vascular events as well. Recent prospective observational studies support the use of statins in older persons, with 44% relative risk reductions in all-cause mortality being reported in patients aged 65 years and older in the Cardiovascular Health Study (19) and in patients aged 65 to 79 years in the Intermountain Heart Collaborative Study (20). In an analysis of a nationally representative cohort of over 40,000 older Medicare beneficiaries hospitalized with MI,

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statins provided a mortality benefit at three years’ follow-up in patients up to age 83 (6). Similarly, a prospective study of 1410 patients aged 60 to 100 years (mean age 81 years) with prior MI and elevated LDL cholesterol in a long-term health care facility showed a 36% reduction (p < 0.0001) in the incidence of new coronary events in individuals treated with statins compared with those receiving no lipid-lowering medication, and these benefits were evident across all age ranges (21). Several other observational studies have also confirmed these findings. Multiple, large-scale randomized clinical trials have unequivocally demonstrated the effectiveness of statins not only in reducing LDL cholesterol, but also in improving clinical outcomes. Subgroup analyses of these trials as well as data from the Heart Protection Study (HPS) (22) indicate that statins reduce the risk of major coronary events irrespective of baseline cholesterol levels. More recently, the Treating to New Targets (TNT) (23) and the Pravastatin or Atorvastatin Evaluation and Infection Therapy— Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) studies have confirmed that a more intensive approach to lipid lowering provides incremental benefit beyond a more moderate lipid-lowering strategy in patients with stable CHD or high-risk acute coronary syndromes (ACS), respectively (24). While it is clear that statins reduce coronary heart disease morbidity and mortality rates and increase overall survival in high-risk individuals younger than 75 years, the impact of statins in patients older than 75 years is less well delineated. In the Scandinavian Simvastatin Survival Study (4S), 4444 men and women up to age 70 with CHD were randomized to simvastatin or placebo and followed for up to 6.2 years. Simvastatin was associated with a 34% decrease in nonfatal MI and CHD death, a 42% decrease in CHD death alone, and a 30% decrease in all-cause mortality. Additionally, coronary procedures as well as cerebrovascular events were reduced in patients receiving simvastatin. These reductions in coronary and vascular endpoints were consistent across age, and there was no diminution of benefit as age increased (25). In the Cholesterol and Recurrent Events (CARE) study, 4129 patients up to age 75 with average cholesterol levels and who had an MI, 3–20 months before the start of the study, were randomized to pravastatin or placebo. The incidence of the primary combined endpoint of CHD death or nonfatal MI was reduced by 24% over a follow-up period of five years, and the benefits of pravastatin in preventing recurrent events were similar across age groups (26). The LongTerm Intervention with Pravastatin in Ischemic Disease (LIPID) trial (27) was a doubleblind, randomized, placebo-controlled study of 9014 subjects, 39% of whom were older than 65 years and had acute MI or unstable angina within the previous 3 months to 3 years. The primary endpoint, coronary mortality, was reduced by 24% (p < 0.0005), and the secondary endpoint of total mortality was reduced by 22% ( p < 0.001). Risk reductions also occurred in the incidence of MI (29%, p < 0.00001) and stroke (19%, p ¼ 0.048) and in the rate of revascularization (20%, p < 0.001). Although the relative risk reduction with pravastatin was somewhat lower in patients aged 70 to 75 years, the absolute risk reduction was similar across age groups. More recently, subgroup analyses from large randomized trials have also demonstrated that an aggressive lipid-lowering approach provides incremental benefit in older as well as younger patients. In the TNT study, treatment with atorvastatin 80 mg compared to atorvastatin 10 mg was associated with reductions in events in patients with stable CHD irrespective of age or sex. Similarly, in the PROVE-IT study, aggressive LDL lowering with atorvastatin 80 mg was associated with improvements in outcomes compared with moderate LDL reduction with pravastatin 40 mg in patients hospitalized with ACS. These results were also consistent irrespective of patient age or sex. In the Anglo-Scandinavian Cardiac Outcomes Trial Lipid Lowering Arm (ASCOTLLA) atorvastatin reduced the risk of nonfatal MI or fatal CHD by 36%, and the hazard

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ratio for atorvastatin therapy was similar in patients older than 60 years (0.64; p ¼ 0.0027) and 60 years and younger (0.66; p ¼ 0.0869) (28). The Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) specifically investigated the benefits of statin treatment in an older population (n ¼ 5804; age 70–82 years) with or at high risk for vascular disease. Pravastatin treatment significantly decreased the risk of CHD death or nonfatal MI by 19% and reduced CHD mortality by 24% (29). There was, however, a significant 25% increase in incident cancer, a finding not confirmed in other studies. The recently reported Study Assessing Goals in the Elderly (SAGE) randomized 893 ambulatory patients aged 65 to 85 years (mean 72.5 years, 31% women) with CHD to receive atorvastatin 80 mg or pravastatin 40 mg daily and followed them for a 12-month period (30). All-cause mortality was 67% lower in the atorvastatin group ( p ¼ 0.014) and there was also a nonsignificant 29% reduction in major cardiovascular events ( p ¼ 0.11). Thus, the efficacy of statin treatment appears to be maintained in high-risk older patients. These studies emphasize that statins are most beneficial in populations with greatest cardiovascular risk. Although relative risk reductions in older persons are similar to those observed in a middle-aged population, older patients are at greater absolute risk of cardiovascular events (25). Therefore, even small relative risk reductions can translate into larger absolute benefits. For example, in two large studies, although relative risk reductions were similar in patients 65 years and older compared with those younger than 65 years, absolute risk reductions were 1.5- to 2-fold greater in older patients (31). The value of statin therapy in lower-risk older persons is the subject of debate. In the PROSPER study, the only trial specifically designed to assess the role of lipid lowering in older persons, pravastatin did not provide benefit in the primary prevention of cardiovascular events in lower-risk patients. However, a recent review of statin studies including PROSPER demonstrated that statins are beneficial in the primary prevention of disease even in patients at very low risk (32).

CHOLESTEROL INTERVENTION AND CEREBROVASCULAR DISEASE PREVENTION The relationship between cholesterol and cerebrovascular events has been difficult to establish. However, data from the Honolulu Heart Study indicate that after adjustment for multiple comorbid conditions, low HDL cholesterol (<40 mg/dL) is associated with a significant hazard for subsequent stroke [hazard ratio (HR) 2.7)] compared with high HDL (>60 mg/dL). Epidemiologic data linking elevated LDL to cerebrovascular events is limited but recent studies and subgroup analyses of large randomized trials have explored the impact of statin therapy for the prevention of stroke. Five major trials of statin therapy included patients without definite evidence of CHD: West of Scotland Coronary Prevention Study (WOSCOPS), Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial-Lipid Lowering Trial (ALLHAT-LLT), HPS, ASCOT-LLA, and Collaborative Atorvastatin Diabetes Study (CARDS). Stroke was a component of the combined primary endpoint in CARDS and a secondary endpoint in the other trials. Active treatment reduced the risk of fatal and nonfatal stroke by 9% to 48%. Similarly, long-term trials of statins that included approximately 90,000 patients with known CHD showed reductions in the relative risk of stroke of up to 50%. Consistent with reductions in the primary cardiovascular endpoints in these trials, statin therapy was associated with a 32% reduction in stroke in the CARE study, a 19% reduction in the LIPID study, and a 50% reduction in the Myocardial Ischemia Reduction with Aggressive

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Cholesterol Lowering (MIRACL) study. In the HPS, simvastatin therapy was associated with a significant 27% reduction in stroke. Several meta-analyses have estimated the overall risk reduction in stroke to be approximately 15–30% (33,34). In addition, although not statistically significant, transient ischemic attacks (TIAs) were reduced by 25% in the PROSPER study ( p ¼ 0.051). On the basis of these findings, the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial was designed to address the question of whether statin therapy would reduce second stroke in stroke survivors (35). In this study, 4731 patients with stroke or TIA within six months, without known CHD, and with LDL cholesterol levels between 100 and 190 mg/dL were randomized to either atorvastatin 80 mg daily or placebo. The primary outcome was recurrent fatal or nonfatal stroke. Secondary endpoints included major coronary or cardiovascular events. Follow-up was planned for five years or until at least 540 events had occurred. The trial showed that high dose atorvastatin was associated with a 16% reduction in the risk of fatal or nonfatal stroke [HR 0.84 (0.71– 0.99), p ¼ 0.03]. Of note, recurrent strokes also tended to be less severe in patients treated with atorvastatin. In addition, major cardiovascular events were reduced by 35% in patients randomized to statin therapy [HR 0.65 (0.49–0.87), p ¼ 0.003]. Given the significant burden of stroke in older persons, statins appear to be a reasonable approach for improving both cardiovascular and cerebrovascular outcomes. CHOLESTEROL INTERVENTION AND VASCULAR DISEASE PREVENTION Atherosclerotic vascular disease, including abdominal aortic aneurysm (AAA), renal artery stenosis, and peripheral arterial disease, is common in older persons and shares many risk factors with CHD, including elevated lipids. Increasing evidence supports the benefits of statin therapy in these disorders. For example, in the HPS, patients with peripheral arterial disease who were treated with simvastatin had a 19% reduction in the rate of new vascular events (22). LDL cholesterol has also been shown to be an independent predictor of the risk of AAA (36), and preclinical studies indicate that cerivastatin suppresses matrix metalloproteinase-9 production by inflammatory cells in the aneurysm wall (37). Hence, in addition to lipid-modifying effects, the antiinflammatory actions of statins may have benefit for the prevention or treatment of AAA. Dyslipidemia and other cardiovascular risk factors have been associated with an increase in the risk of aortic stenosis (38). Moreover, observational studies suggest that statin therapy may slow the rate of progression of aortic stenosis as measured by aortic valve area (39) or accumulation of aortic calcium (40). However, in a randomized trial involving 155 patients with calcific aortic stenosis, mean age 68 years, atorvastatin 80 mg daily failed to reduce the rate of progression compared with placebo over 25 months’ follow-up (41). More recently, an open-label study of 121 patients, mean age 74 years, with moderate aortic stenosis randomized to rosuvastatin 20 mg daily or placebo showed that rosuvastatin slowed the rate of echocardiographic progression of aortic stenosis during an average follow-up period of 17 months (42). In light of these conflicting results, the ongoing Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial, which has randomized 1873 patients with asymptomatic aortic stenosis (mean age 68 years) to combination therapy with simvastatin 40 mg and ezetimibe 10 mg daily or to placebo, with a planned minimum follow-up of four years, should provide definitive information on the role of lipid-lowering therapy in older adults with moderate aortic stenosis (43).

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CHOLESTEROL INTERVENTION AND COGNITIVE FUNCTION Atherosclerosis is considered to be one of the mechanisms underlying the development of cognitive functional impairment in some patients (44), and elevated plasma cholesterol levels in middle age have been reported to increase the risk of Alzheimer’s disease later in life (45). In addition, several observational and cross-sectional studies have reported beneficial neurological effects with statins. For example, one crosssectional study showed that statin treatment was associated with a 70% lower prevalence of dementia (46). A retrospective study of a community-based population also demonstrated an association between statin use and reduced rates of dementia (47). Similarly, a population-based Canadian survey found that lipid-lowering therapy was associated with a reduced risk of Alzheimer’s disease in patients younger than 80 years (48). Finally, in the Heart and Estrogen/progestin Replacement Study, cognitive impairment was associated with elevated LDL levels and patients receiving statin treatment recorded higher modified Mini-Mental State Examination (MMSE) scores and tended to have a lower likelihood of cognitive impairment than individuals not on statin therapy (49). Although these observations are promising, they have yet to be confirmed by prospective randomized trials. The effect of pravastatin treatment in older persons was investigated in PROSPER and no significant reduction in the risk of cognitive decline was reported. CHOLESTEROL INTERVENTION AND HEART FAILURE Heart failure (HF) is a major and growing public health problem worldwide (50,51). Cross-sectional and population-based studies indicate that at least one-third to one-half of all patients with HF have minimally reduced or preserved systolic function (PSF) (52). HF with PSF primarily affects older persons and is associated with poor prognosis (52). As the world population ages, the incidence and economic impact of HF with PSF will continue to increase. Unfortunately, no therapy to date has been shown to improve survival in these patents. An emerging body of evidence suggests the potential value of statins in the management of patients with HF and reduced systolic function (53–56); however, data for patients with HF and PSF are very limited. A recent small single center study suggested that statin therapy may improve survival in patients with HF and PSF (57). In this study, 137 patients (68 on a statin and 69 on no statin) were followed for 21  12 months. After adjustment for differences in baseline clinical variables between groups (hypertension, diabetes, coronary artery disease, and serum creatinine), statin therapy was associated with lower mortality (relative risk of death, 0.20; 95% CI, 0.06 to 0.62). However, the small sample size and single site nature of this study limit its generalizability. There are several possible mechanisms by which statin therapy may produce beneficial effects in HF patients. Statin therapy has been shown to reduce myocardial necrosis and preserve myocardial viability (58), improve ventricular remodeling (59–62), prevent or even regress left ventricular hypertrophy and fibrosis (63), and down-regulate angiotensin type 1 receptors (64), all of which have important implications for HF patients. Statins may also improve left ventricular relaxation and diastolic function by decreasing left ventricular afterload via several mechanisms, including increasing arterial distensibility (65,66), improving endothelial function (67), decreasing blood pressure (59,60), modulating endothelial nitric oxide synthesis (61,62), and improving impaired autonomic nervous system activation (68). Most recently, statin use has been associated

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with a reduced incidence of atrial fibrillation (69,70), a prevalent condition in older persons with or without HF.

SPECIAL CONSIDERATIONS FOR CHOLESTEROL INTERVENTIONS IN THE ELDERLY The most recent edition of the National Cholesterol Education Program (NCEP) guidelines utilizes estimates of cardiovascular risk derived from Framingham tables relating levels of individual risk factors to coronary risk (71). In this scoring system, age is the single most potent predictor of risk. As a result, older individuals, even with only modest abnormalities of other risk factors, are more likely to fall into categories for which treatment with drugs to lower cholesterol is indicated. However, the decision to treat an older patient requires a careful balance between potential benefits and harms. Although statin therapy is effective in many older patients, some subgroups of older persons may not benefit. Kaplan-Meier curves from clinical trials indicate that the benefits of statin treatment can take up to one to two years to become apparent. Therefore, statin treatment may be unlikely to benefit patients with a short life expectancy (<2 years). However, persons aged 65 to 80 years in otherwise good health have sufficiently long life expectancies to benefit from statin treatment. Studies like PROSPER and HPS have improved the evidence base for statin treatment in patients up to and beyond 80 years of age and therefore help guide clinical decisions. Issues surrounding the underuse of statins in older persons need to be addressed, as these agents have been shown to be well tolerated and effective at reducing CHD morbidity and mortality. Older individuals are particularly susceptible to adverse effects because they often receive concomitant medications, have comorbid conditions and competing risks, or may have impaired ability to metabolize and excrete compounds as a result of declining renal and hepatic function. Consequently, the safety of any lipid-lowering agent is particularly important for these patients, and physicians need to be aware of possible drug interactions. Several overarching principles must be considered when treating older persons in general and with statins specifically. While older persons account for only 13% of the population, they account for more than one-third of individuals utilizing prescription drugs. It is estimated that older adults fill an average of 5.7 prescriptions per year. It is also estimated that approximately 15% of all hospitalizations in older persons are related to adverse drug reactions. The more medications a person is prescribed, the more likely it is that a drug-drug interaction or adverse drug reaction will occur. Thus, polypharmacy and the potential for drug-drug interactions are of the utmost concern in this patient population. With aging, the pharmacokinetics of virtually all drugs are impacted and statins are no exception. This is due in part to the decline in total body water related to decreased muscle mass and the concomitant increase in total body fat, which ultimately affects the volume of distribution for almost all drugs. Water-soluble drugs are likely to have increased serum levels, while fat-soluble drugs have increased availability because of a prolonged half-life caused by the increased proportion of total body fat. To further complicate matters, there are variable changes in first-pass metabolism due to a variable decline in hepatic blood flood—thus elders may have less first-pass effect than younger persons, although this is difficult to predict on an individual basis. Moreover, oxidative metabolism through the cytochrome P450 (CYP) system declines with aging, resulting in decreased clearance of many drugs. This effect, coupled with increased likelihood of exposure to multiple medications that are metabolized through the P450 system, leads to increased potential for elevated serum levels of drugs and associated toxicity.

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Despite these concerns, statin therapy is generally well tolerated in older persons. For example, simvastatin therapy was associated with relatively few side effects in the HPS, which included a large population of older patients who were taking concomitant medications (72). The Cholesterol Reduction In Seniors Program (CRISP) pilot study also showed that lovastatin 20 to 40 mg daily was associated with preserved health-related quality of life relative to placebo in a cohort of older adults with a mean age of 71 years (73). In a recent analysis from the TNT study, treatment with 80 mg of atorvastatin provided significant clinical benefit compared with 10 mg of atorvastatin in participants with stable coronary artery disease. There was a 2.3% absolute reduction in major cardiovascular events and a 19% relative reduction in risk favoring the high-dose group ( p ¼ 0.032). These findings support the use of intensive LDL cholesterol-lowering therapy in high-risk older persons with established cardiovascular disease (74). Although the frequency of serious adverse events, such as severe myopathy, with statin treatment is low (<0.5%), older subjects may be more susceptible. Drug exposure in muscle tissue may be increased in older patients as a result of the age-related decline in muscle mass. In addition, hypothyroidism, which is more common in older persons, increases the risk of statin-induced myopathy. Hence, both physicians and patients should be alert to the presence of persistent myalgias, muscle tenderness, and particularly myoglobinuria. Physicians may be able to reduce the likelihood of adverse events by their choice of statin. It has been suggested that the lipophilicity of some statins may influence their entry into muscle tissue. Hydrophilic statins, such as lovastatin and pravastatin, are likely to penetrate muscle tissue to a lesser degree than lipophilic statins, such as atorvastatin, fluvastatin, and simvastatin, and may therefore be less likely to cause myotoxic events (75). The potential for myotoxicity is also determined in part by systemic bioavailability, which is relatively low for statins (5–24%), and this limits the exposure of muscle tissue to these agents. The route of metabolism may also influence the likelihood of drug interactions and adverse effects. CYP 3A4 is the most abundant (60%) hepatic enzyme and is responsible for metabolizing the widest range of drugs (76). Thus, statins metabolized through pathways other than CYP 3A4 may be expected to have fewer drug interactions, which may be an advantage in older persons. However, the withdrawal of cerivastatin as a result of deaths due to rhabdomyolysis, particularly when coadministered with gemfibrozil, highlights the importance of drug interactions mediated by pathways other than CYP 3A4. In addition to side effects and drug interactions, recent concerns have been raised over whether statin use may be associated with increased rates of certain cancers. In a meta-analysis of 26 randomized controlled trials of sufficient size and duration and which reported data on cancer diagnosis or cancer death, Dale et al. evaluated the effect of statins on cancer in general and on specific types of cancer (77). Individual statin brands as well as pharmacologic characteristics (hydrophilic vs. lipophilic, synthetic vs. natural) were also examined to determine whether there was heterogeneity in cancer effect. Among 86,936 participants included in the analysis, there were 6662 incident cancer cases and 2407 cancer deaths. No statistically significant differences were seen between patients randomized to statins compared with those randomized to control. In addition, there were no differences in cancer rates when the data were stratified according to cancer type, statin brand, dose, or pharmacologic characteristics. These results should reassure clinicians regarding the potential carcinogenic effects of statins, but they also emphasize that statins should not be viewed as effective anticancer agents. Despite the potential benefits of lipid lowering on cardiovascular events, many patients are not receiving optimal treatment, and undertreatment of lipid levels is especially prevalent in older individuals. For example, a 29% prevalence of lipid-lowering drug use

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was observed in male CHD patients aged 60 to 75 years, and only 12% achieved total cholesterol levels recommended by the NCEP guidelines (6). Statin treatment appears to be prescribed preferentially to individuals under the age of 65 years, and an inverse relationship between age and the use of lipid-lowering medication has been observed in patients with CHD in the United States and Canada (78). Several factors may contribute to lower statin prescription rates in older patients. As old age has traditionally been associated with high rates of mortality and morbidity, clinicians may believe that older persons are less likely to benefit from treatment. However, with the present high quality of health care and increased survival, many patients remain active and independent into old age. Another reason for undertreatment of lipids in older persons is a perceived lack of evidence that statins are effective or beneficial in this population. However, with the publication of HPS and PROSPER, there is now a strong scientific basis for treating patients aged 65 to 80 years, especially those at moderate or high risk for cardiovascular events. Similarly, many patients older than 80 years with cardiovascular disease or older than 65 years at risk for cardiovascular disease (i.e., primary prevention) are at sufficiently high risk to benefit from statin treatment, and better methods of identifying these individuals are required. Unfortunately, there is currently little scientific evidence to guide treatment decisions for very old patients (>85 years). Another factor that may contribute to the underuse of statins is concern about the cost-effectiveness of treatment in this age group. However, studies indicate that the costeffectiveness of statins is similar in younger and older patients. For example, analysis of CHD and stroke risk reductions with statin treatment for secondary prevention indicate incremental cost-effectiveness ratios ranging from $4675 to $20,987 per year of life gained in men and women 40 years of age, and from $7447 to $21,719 in men and women 70 years of age (79). All of these estimates are well within the generally accepted cost-effectiveness benchmarks in the United States of $50,000 to $100,000 per year of life gained. Adherence to therapy can be particularly poor in older patients owing to polypharmacy, medication costs, depression, or cognitive decline. Physicians may improve compliance by educating patients and their families or caregivers about the importance of adhering to therapy. The use of more efficacious, well-tolerated statins enabling a greater proportion of patients to achieve cholesterol targets on the initial dose, thereby reducing the need for titration, may aid compliance in both older and younger patients. HDL CHOLESTEROL Although LDL cholesterol is considered the predominant atherogenic lipoprotein in the development of CHD, there is considerable variability in the clinical expression of CHD at any given LDL concentration. HDL cholesterol levels exhibit a continuous and inverse relationship with CHD events, although data in older persons are scant. In the Framingham Heart Study, a low level of HDL was an independent predictor of CHD (80). In fact, at all levels of LDL cholesterol, the level of HDL influenced the risk of developing CHD. In men with HDL levels less than 25 mg/dL, the CHD incidence over four years was 180/1000 compared with 25/1000 in men with HDL levels greater than 64 mg/dL. A similar relation was noted in women, and these relationships persisted above the age of 60 years. Other studies have reported similar findings. In general, a 1 mg/dL increase in HDL is associated with a reduction in CHD risk of approximately 2% in men and 3% in women. The HDL level has no effect on noncardiovascular disease mortality. The Lipid Research Clinics Coronary Primary Prevention Trial (81–84) using cholestyramine and the Helsinki Heart Study (85) using gemfibrozil both demonstrated that increasing HDL lowered CHD events, and this association was independent of any

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effect on LDL. More recently, the VA HDL Intervention Trial (VA-HIT) and Bezafibrate Infarction Prevention (BIP) trial demonstrated that increasing HDL reduces CHD mortality (86,87). The ATP III of the NCEP identifies low HDL cholesterol as a major risk factor for CHD and recommends that all healthy adults be screened for both total cholesterol and HDL cholesterol levels. Triglycerides The independent relationship between plasma triglycerides (TGs) and CHD has now been established (88), although data in older persons are again limited. It is likely that the defective lipoprotein metabolism involved in hypertriglyceridemia may create a vascular environment predisposed to atherogenesis. Elevated fasting plasma TG is a hallmark of insulin resistance syndrome, a metabolic disorder characterized by hyperinsulinemia, glucose intolerance, decreased HDL, and possibly central obesity and increased production of atherogenic, small, dense LDL particles. Data from the observational Prospective Cardiovascular Muenster (PROCAM) (89) study showed that CHD risk is high when TG levels exceed 200 mg/dL and the total cholesterol/HDL ratio is greater than 5 because of low HDL (<35 mg/dL). In this eightyear prospective study of 4639 German males, aged 40 to 65 years, the incidence of major coronary events steadily increased in association with rising TG levels up to 800 mg/dL. Patients with TG > 200 mg/dL had at least twice the coronary event rate as patients with normal TG levels. However, despite these data, and the fact that fibric acid derivatives, nicotinic acid, and fish oil capsules effectively lower TGs, there is currently no evidence that treatment of elevated TG levels lowers cardiovascular risk. For this reason, TGs are considered a secondary target for lipid-lowering therapy in current NCEP guidelines. NONSTATIN APPROACHES TO LIPID LOWERING Diet A proper diet, rich in fruits, vegetables, and whole grain foods and low in saturated and transsaturated fats, is an integral component of lipid-lowering therapy. NCEP and American Heart Association (AHA) guidelines promote a diet in which fat composes 30% or less of total calories. Based on recommendations from the World Health Organization, the AHA suggests that fat calories constitute no less than 15% of total calories. A change from the average American diet to the AHA’s Step-One Diet, in which less than 10% of total calories are derived from saturated fatty acids and dietary cholesterol intake is less than 300 mg/dL, reduces serum cholesterol levels by approximately 7%. Further restriction to less than 7% of calories from saturated fatty acids and less than 200 mg/dL of cholesterol (Step-Two Diet) reduces cholesterol levels by an additional 3% to 7%. Exercise Regular exercise is important for maintaining cardiovascular fitness, particularly in older adults, and low levels of physical activity are associated with an increased risk for both cardiovascular events and all-cause mortality. However, large epidemiologic studies have failed to demonstrate a consistent correlation between reported physical activity and lipid values. On the other hand, exercise interventions have been shown to improve functional capacity, raise HDL, and lower TG levels, thereby favorably altering the cardiovascular risk profile. In addition, exercise-based cardiac rehabilitation programs reduce the risk of

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recurrent cardiac events, including death, following acute MI or coronary bypass surgery. Therefore, regular exercise is recommended in conjunction with a healthy diet and weight loss as part of an overall strategy for improving health and reducing cardiovascular risk. Pharmacotherapy Currently, LDL remains the principal target for intervention, and efforts to reduce cardiovascular risk should first focus on reducing LDL cholesterol in accordance with existing guidelines. HDL, TGs, and non-HDL cholesterol (i.e., total cholesterol – HDL cholesterol) levels are secondary targets for intervention once the appropriate LDL level has been achieved. Unfortunately, because of the paucity of clinical trials addressing either HDL-raising or TG-lowering therapies, evidence-based recommendations are lacking, and data in older persons are essentially nonexistent. Beyond statins, pharmacological interventions include nicotinic acid, fibric acid derivatives, and ezetimibe. Each has a unique mechanism of action and potential side effect profile in older persons. Nicotinic Acid Nicotinic acid (niacin) is a B vitamin that inhibits adenylate cyclase when administered in high doses, thereby affecting the lipoprotein system mediated through nicotinamide adenine dinucleotide (NAD), or NADP. Rapid release of prostaglandins from platelets is thought to be responsible, in part, for the vasodilation and flush response commonly associated with high dose niacin therapy. Nicotinic acid exerts favorable effects on HDL, TGs, TG-rich lipoproteins, total cholesterol, LDL, LDL subclass pattern B, and possibly lipoprotein(a) [Lp(a)]. In daily doses of 1500 to 3000 mg, nicotinic acid typically reduces total cholesterol and LDL levels by 10% to 25% and TG levels by up to 50%, while increasing HDL by 15% to 30%. Nicotinic acid is the lipid-altering drug with the most potential for side effects and, consequently, adherence problems. However, given the potential benefits of the drug, it is worth expending extra effort to achieve compliance in well-selected individuals. Slowly titrating the dose from 100 to 500 mg three times a day over a one-month period can ease the patient into a therapeutic dose range. The prostaglandin-mediated flush reaction, which occurs in up to 50% of patients, can be ameliorated in part by ingesting 2.5 grains (162.5 mg) of aspirin 15 minutes prior to niacin dosing. Avoiding alcohol, monosodium glutamate, hot beverages, and spicy foods can also help minimize flushing. Once daily sustained-release niacin preparations also appear to be associated with less flushing, especially when taken at bedtime. Other side effects from high dose niacin include a small increase in the serum glucose level (average 6%), a moderate increase in the serum uric acid level, and a small reduction in the serum phosphorus level. Significant elevations in hepatic transaminases are uncommon with niacin monotherapy. Combination Therapy with Statins and Nicotinic Acid Several large studies have assessed the effects of combining a statin with nicotinic acid. In the Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2 study (90), niacin (1000 mg/day) was added to statin therapy (majority of subjects used simvastatin) in persons with known CHD. The mean age of the study population was 67  10 years, and 91% were men. Progression of carotid intimal-medial

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thickness was significantly less in subjects using the statin-niacin combination compared to a statin alone. LDL cholesterol levels were less than 100 mg/dL in both groups, while HDL increased significantly (17%, p ¼ 0.003) and TG decreased significantly (18%, p ¼ 0.03) in the statin-niacin group. Fasting glucose levels increased in both groups, while flushing was more common in the statin-niacin group. In another study (91), the effect of statin-niacin therapy on calcified plaque progression was assessed in subjects without known CHD. The investigators found no difference in calcium burden as assessed by electron beam computed tomography between statin-only and statin-niacin therapy. HDL cholesterol increased in the statinniacin group, while levels of LDL, non–HDL cholesterol, TGs, and total cholesterol: HDL decreased significantly. In a more recent study assessing the effects of rosuvastatin and extended-release niacin (92) in subjects with mixed dyslipidemia, the rosuvastatin/ extended-release niacin combination was well tolerated and significantly reduced total cholesterol and TG levels while increasing HDL levels. Fibric Acid Derivatives Fibric acid derivatives (fibrates) enhance lipoprotein lipase activity and hepatic bile secretion and reduce hepatic TG production. TG reductions between 8% and 72%, LDL reductions between 1% and 35%, and HDL increases between 1% and 25% have been reported. These agents are useful in the treatment of hypertriglyceridemia and in selected patients who have elevated LDL in combination with elevated TGs. The HDL level often increases when the initial HDL is low. In the Helsinki Heart Study, gemfibrozil 600 mg twice daily resulted in an overall 42% reduction in TGs, 10% reduction in LDL, and a 10% increase in HDL (85). These effects led to a 34% reduction in the incidence of CHD, although there was no difference in total mortality (93). Fibrates are generally well tolerated. Occasionally, mild nausea is experienced during the first week of therapy. To reduce this potential side effect, it can be useful to start treatment with one-half the normal dose for several days before increasing to a full dose. Fibric acid derivatives are excreted primarily through the kidney; therefore the dose should be adjusted in patients with chronic kidney disease. In addition, warfarin should be dosed at one-third its standard dose when administered with fenofibrate, with careful follow-up of the international normalized ratio. Glucose tolerance is not impacted by this agent, and no lithogenic potential has been observed. Creatine phosphokinase elevations are noted in 0.6% to 1.1% of cases, usually in association with renal failure. Liver enzymes increase in less than 2% of cases, whereas gastrointestinal disturbances (constipation, dyspepsia, and diarrhea) account for over 50% of side effects, leading to discontinuation in 3.5% of patients. Combination Therapy with Statins and Fibrates Product information for statins and fibrates generally states that combination therapy with these agents is not recommended, owing to an increased risk of myopathy. Combination therapy must be used with care and should probably be avoided in all but the healthiest older people. In particular, patients with acute or serious chronic illness (especially renal disease), those requiring surgery, and those on multiple medications or cyclosporin, macrolides, or antifungals, should not take both a statin and a fibrate. However, despite these precautions, excellent therapeutic responses can be achieved with appropriate safety monitoring. In a literature review regarding the safety of combination therapy with statins and fibrates in the treatment of mixed hyperlipidemia in patients aged 44 to 64 years (mean

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age for all trials, 53.3  5.6 years), the incidence of myopathy was 0.12% (defined as creatine kinase levels >10 times the upper limit of normal) (94). Musculoskeletal symptoms (myalgia, muscle weakness, musculoskeletal pain, or myositis) occurred in 1.9%, subclinical elevations of creatine kinase (elevations <10 times the upper limit of normal) occurred in 2.1%, and subclinical elevations of serum transaminases (elevations <3 times the upper limit of normal) occurred in 3.2%. Gemfibrozil was the most prescribed fibrate (56%) in this study, whereas fenofibrate usage accounted for only 6% of the total (the remainder of the fibrates used, including bezafibrate and ciprofibrate, are not available in the United States). Overall, older age, female gender, renal or liver disease, diabetes, hypothyroidism, debilitated status, surgery, trauma, excessive alcohol intake, and heavy exercise were associated with increased risk for myopathy. Ezetimibe Ezetimibe selectively inhibits the intestinal absorption of cholesterol and related phytosterols. Administered alone or in combination with a statin, ezetimibe is indicated as adjunctive therapy to diet for the reduction of elevated total cholesterol, LDL, and apolipoprotein B in patients with primary hypercholesterolemia. Mechanistically, the combination of a statin, which inhibits hepatic cholesterol synthesis, and ezetimibe, which blocks intestinal cholesterol absorption, is attractive (95,96), and several studies have shown that combination therapy is more effective than either drug class alone in lowering total cholesterol and LDL levels, and in achieving target LDL levels recommended by current guidelines (95–106). The effect of this strategy on cardiovascular outcomes, however, has not been established. Ezetimibe is generally well tolerated. When coadministered with a statin, elevations in serum transaminases (>3 times the upper limit of normal) occur slightly more frequently (1.3%) than with a statin alone (0.4%). Therefore, liver function tests should be monitored when ezetimibe is added to statin therapy. Rhabdomyolysis has been reported very rarely with ezetimibe monotherapy or when ezetimibe has been added to a statin. The safety and effectiveness of ezetimibe in combination with fibrates have not been established; therefore, coadministration with fibrates is not recommended. In addition, limited data are available on the use of ezetimibe in older adults, either as a single agent or in combination with a statin. CONCLUSION With increases in life expectancy and the rapid growth of the population over the age of 80 years, it has become imperative to maintain quality of life and reduce morbidity. Data from several studies indicate that statin treatment reduces total and LDL cholesterol levels and the risk of cardiovascular disease as effectively in older high-risk individuals as in younger individuals. However, despite these benefits, a substantial proportion of older individuals at risk for cardiovascular events are not receiving evidence-based lipidlowering therapy. Physicians should use clinical judgment in determining who should receive lipid-lowering treatment, basing their decisions on patient preferences, individual outcome goals, life expectancy, and quality of life, coupled with the anticipated benefits and potential risks of therapy, including cost-effectiveness. Further studies exploring the role of lipid lowering in the very old as well as in primary prevention of cardiovascular disease in older persons are necessary. For now, a large body of consistent data indicates that patients should not be denied lipid-lowering therapy solely on the basis of age.

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85. Manninen V, Tenkanen L, Koskinen P, et al. Joint effects of serum triglycerides and LDL cholesterol and HDL cholesterol concentrations on coronary heart disease risk in the Helsinki Heart Study—implications for treatment. Circulation 1992; 85:37–45. 86. Rubins HB, Robins SJ, Collins D, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. N Engl J Med 1999; 341:410–418. 87. Goldenberg I, Goldbourt U, Boyko V, et al. Relation between on-treatment increments in serum high-density lipoprotein cholesterol levels and cardiac mortality in patients with coronary heart disease (from the Bezafibrate Infarction Prevention trial). Am J Cardiol 2006; 97(4):466–471. 88. Assmann G, Schulte H. Role of triglycerides in coronary artery disease: lessons from the Prospective Cardiovascular Muenster Study. Am J Cardiol 1992; 70:10H–13H. 89. Assmann G, Schulte H. Obesity and hyperlipidemia: results from the Prospective Cardiovascular and Muenster (PROCAM) study. In: Bjorntorp P, Brodoff B, eds. Obesity. JB Lippincott, New York, 1992:502–511. 90. Taylor AJ, Sullenberger LE, Lee HJ, et al. Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2: a double-blind, placebo-controlled study of extended-release niacin on atherosclerosis progression in secondary prevention patients treated with statins. Circulation 2004; 110:3512–3517. 91. Wink J, Giacoppe G, King J. Effect of very-low-dose niacin on high-density lipoprotein in patients undergoing long-term statin therapy. Am Heart J 2002; 143:514–518. 92. Capuzzi DM, Morgan JM, Weiss RJ, et al. Beneficial effects of rosuvastatin alone and in combination with extended-release niacin in patients with a combined hyperlipidemia and low high-density lipoprotein cholesterol levels. Am J Cardiol 2003; 91:1304–1310. 93. Frick MH, Elo O, Haapa K, et al. Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med 1987; 317(20):1237–45. 94. Shek A, Ferrill MJ. Statin-fibrate combination therapy. Ann Pharmacother 2001; 35:908–917. 95. Feldman T, Koren M, Insull W Jr, et al. Treatment of high-risk patients with ezetimibe plus simvastatin co-administration versus simvastatin alone to attain National Cholesterol Education Program Adult Treatment Panel III low-density lipoprotein cholesterol goals. Am J Cardiol 2004; 93:1481–1486. 96. Goldberg AC, Sapre A, Liu J, et al. Efficacy and safety of ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia: a randomized, double-blind, placebo-controlled trial. Mayo Clin Proc 2004; 79:620–629. 97. Pearson TA, Denke MA, McBride PE, et al. A community-based, randomized trial of ezetimibe added to statin therapy to attain NCEP ATP III goals for LDL cholesterol in hypercholesterolemic patients: the Ezetimibe Add-on to Statin for Effectiveness (EASE) trial. Mayo Clin Proc 2005; 80(5):587–595. 98. Lipka L, Sager P, Strony J, et al. Efficacy and safety of coadministration of ezetimibe and statins in elderly patients with primary hypercholesterolemia. Drugs Aging 2004; 21 (15):1025–1032. 99. Ballantyne CM, Houri J, Notarbartolo A, et al. Effect of ezetimibe coadministered with atorvastatin in 628 patients with primary hypercholesterolemia: a prospective, randomized, double-blind trial. Circulation 2003; 107(19):2409–2415. 100. Davidson MH, McGarry T, Bettis R, et al. Ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia. J Am Coll Cardiol 2002; 40(12):2125–2134. 101. Ballantyne CM, Blazing MA, King TR, et al. Efficacy and safety of ezetimibe co-administered with simvastatin compared with atorvastatin in adults with hypercholesterolemia. American J Cardiol 2004; 93(12):1487–1494. 102. Gotto AM Jr., Farmer JA. Drug insight: the role of statins in combination with ezetimibe to lower LDL cholesterol. Nature Clinical Pract 2006; 3(12):664–672.

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103. Barrios V, Amabile N, Paganelli F, et al. Lipid-altering efficacy of switching from atorvastatin 10 mg/day to ezetimibe/simvastatin 10/20 mg/day compared to doubling the dose of atorvastatin in hypercholesterolemic patients with atherosclerosis or coronary heart disease. Int J Clinical Pract 2005; 59(12):1377–1386. 104. Kerzner B, Corbelli J, Sharp S, et al. Efficacy and safety of ezetimibe coadministered with lovastatin in primary hypercholesterolemia. Am J Cardiol 2003; 91(4):418–424. 105. Ballantyne CM, Abate N, Yuan Z, et al. Dose-comparison study of the combination of ezetimibe and simvastatin (Vytorin) versus atorvastatin in patients with hypercholesterolemia: the Vytorin Versus Atorvastatin (VYVA) study. Am Heart J 2005; 149(3):464–473. 106. Bays HE, Ose L, Fraser N, et al. A multicenter, randomized, double-blind, placebo-controlled, factorial design study to evaluate the lipid-altering efficacy and safety profile of the ezetimibe/ simvastatin tablet compared with ezetimibe and simvastatin monotherapy in patients with primary hypercholesterolemia. Clin Ther 2004; 26(11):1758–1773.

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Diabetes Mellitus and Cardiovascular Disease in the Elderly Gabriel Gregoratos and Gordon Leung University of California, San Francisco, California, U.S.A.

Diabetes mellitus is the most common metabolic disorder in the United States, affecting over 20 million persons, and more than 650,000 new cases are diagnosed annually (1,2). More than 100 million people are affected worldwide; approximately 90% of these have the non-insulin-dependent type of the disease. The prevalence of diabetes mellitus increases with advancing age and is estimated to be 20% in Caucasians older than 75 years. Because of its serious long-term complications, diabetes mellitus has become a major public health problem (3,4). The sequelae of diabetes mellitus are commonly divided into microvascular (mainly retinopathy, nephropathy, and neuropathy) and macrovascular (atherosclerotic disease of the coronary, cerebral, and peripheral arterial circulation). Multiple clinical studies over the years have documented the increased risk of diabetic patients to develop cardiovascular disorders. The Framingham Study of more than 5000 subjects showed diabetes mellitus to be a powerful risk factor for atherosclerotic coronary and peripheral vascular diseases with relative risks (RR) averaging twofold for men and threefold for women (5). The Framingham Study also showed that the risk of stroke is 2.5 times higher than average in diabetics (6). These findings have been confirmed by other epidemiological studies such as the Honolulu Heart Program, the Copenhagen Stroke Study, the Rancho Bernardo Study, and the Monitoring of Trends and Determinants in Cardiovascular Diseases (MONICA) study (7–9). More recently, a population-based study of elderly patients concluded that diabetes mellitus is also an independent risk factor for heart failure and that the risk of heart failure increases with disease severity (10). In a recent meta-analysis of 37 prospective studies that included 447,064 patients, the overall rate of fatal coronary heart disease (CHD) during follow-up periods ranging from 4 to 36 years was 5.4% for diabetics versus 1.6% for nondiabetic patients (11). Because of the compelling evidence of the impact diabetes has on the development of CHD, it has been upgraded in the most recent version of the Adult Treatment Panel (ATP) III of the National Cholesterol Education Program (NCEP) guidelines from a simple cardiovascular risk factor to a CHD-risk equivalent; this means that the future cardiovascular risk of a diabetic is comparable to that expected in a patient with established atherosclerotic disease (12). 179

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Epidemiological studies of diabetes mellitus have shown that gender, age, and ethnic background are important factors when considering the development of diabetic complications. In a population study from Sweden of diabetes as a risk factor for acute myocardial infarction (MI), the prevalence of diabetes was 5% in men and 4.4% in women (13). The RRs for MI were 2.9 [confidence interval (CI) 2.6–3.4] in diabetic men and 5.0 (CI 3.9–6.3) for diabetic women. Overall acute MI mortality was four times higher in diabetic men and seven times higher in diabetic women. These and other data have led to the concept that diabetes mellitus causes a loss of the “female advantage” for women (14). However, this concept has recently been challenged. In a meta-analysis of 16 studies, Kanaya et al. found that there was no excess risk of CHD mortality in diabetic women after adjusting for classic CHD risk factors; moreover, men had more CHD deaths attributable to diabetes than women (15). The clinical and economic burden of diabetes mellitus and its complications increases with advancing age. For example, in a group of patients with a mean age of 80
8 years seen in an academic geriatric practice in 2003 (16), the overall prevalence of diabetes was 17%, and the prevalence of target organ damage and/or clinical cardiovascular disease was 85% among the 335 patients with diabetes mellitus. In this elderly group of diabetic patients, 44% had coronary artery disease, 28% had sustained cerebrovascular accidents or transient ischemic attacks, 26% had peripheral vascular disease, 75% had hypertension, 90% had hypertension or hyperlipidemia, 19% had congestive heart failure, 32% had nephropathy, and 20% had retinopathy. The prevalence of diabetes mellitus was highest among Hispanics (29%), lowest in whites (11%), and intermediate in African-Americans (21%). The overall costs of diabetes mellitus constitute a major burden on the United States and worldwide economies. In addition to being a significant cause of cardiovascular disease, diabetes is the leading cause of renal failure in the United States and is responsible for over one-half of the nontraumatic lower limb amputations performed annually (17). Direct and indirect costs of diabetes mellitus account for nearly 15% of total U.S. health care expenditure and were estimated at $132 billion in 2002 (18). Direct medical expenditures totaled to $91.8 billion, including $23.2 billion for diabetes care, $24.6 billion for chronic complications attributable to diabetes, and $44.1 billion for excess prevalence of chronic medical conditions. Of the estimated total $91.8 billion health care expenditures attributable to diabetes, 52% was for services provided to persons 65 years of age or older. These costs are primarily due to the macrovascular and microvascular complications of type 2 diabetes mellitus. In a retrospective cohort study from a large health maintenance organization, the average annual cost of health care for a patient over the age of 65 was $3400 (in 1995). Excess expenditures (expressed as a multiple of the average annual cost) for patients with diabetes mellitus ranged from 1.6 times in those with no diabetic complications to 4.1 times for those with MI, 4.0 times for those with foot ulcers, and 4.3 times for those with end-stage renal disease (19). These data support the notion that early and aggressive preventive and therapeutic interventions in patients with diabetes mellitus and cardiovascular disease are desirable for economic as well as clinical reasons.

PATHOPHYSIOLOGY AND BIOCHEMICAL DEFECT OF DIABETES MELLITUS AND INSULIN RESISTANCE The current classification of diabetes as either type 1 or type 2 is based on the pathophysiological differences between the two syndromes. In type 1 diabetes, hyperglycemia occurs because of the complete inability to produce insulin. In type 2

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diabetes, hyperglycemia is the result of impaired insulin release and an increased resistance to insulin. The majority of the U.S. diabetic population has type 2 diabetes (over 90%). The pathogenesis of both forms of diabetes is complex, being influenced both by genetic and environmental factors. Type 1 Diabetes Mellitus Type 1 diabetes mellitus results from the autoimmune destruction of pancreatic insulinsecreting b cells within the islets of Langerhans. Islet-cell autoantibodies are detected in 80% of patients with newly diagnosed type 1 diabetes, and the measurement of serum isletcell autoantibodies is a screening test to determine patients at risk for this disorder (20). The importance of genetics in the development of type 1 diabetes is supported by the observation that the incidence is increased in relatives of type 1 diabetics. Whereas the lifetime risk for type 1 diabetes is 6% in children, the risk is only 0.4% in families with no diabetes history. An identical twin has a 30% lifetime risk of developing diabetes, while a sibling or fraternal twin has a 5% risk (21). Although four genes have been identified that increase the susceptibility to type 1 diabetes, none of these genes directly induces the disease. The role of environmental factors in the pathogenesis of type 1 diabetes is suggested by twin studies, which have demonstrated that when one monozygotic twin is affected, the other twin is affected less than 50% of the time. Type 2 Diabetes Mellitus Similar to type 1 diabetes mellitus, the pathogenesis of type 2 diabetes is multifactorial, with its development influenced both by environment (particularly diet, obesity, increased visceral fat, advanced age, low exercise level) and genetics (specifically the combined effects of multiple gene alterations). The majority of type 2 diabetics are obese and over the age of 40. Unlike absolute absence of insulin in type 1, type 2 diabetes mellitus is characterized by a combination of both relative deficiency of insulin and insulin resistance. Type 2 diabetes develops when the resistance to insulin activity is no longer compensated by increased insulin production from poorly functioning pancreatic islet b cells. Indeed, insulin resistance may be the best predictor of future type 2 diabetes (22). Sedentary lifestyle and obesity dramatically increase the risk of type 2 diabetes by increasing insulin resistance. Specific biochemical changes affect the prevalence of type 2 diabetes in the elderly. The presence of inflammation as measured by C-reactive protein (CRP) and other proinflammatory cytokines has been associated with the development of diabetes in the elderly (23–25). Conversely, high levels of adiponectin—an adipocytokine that increases insulin sensitivity—are associated with a reduced incidence of diabetes in older age groups (24). Insulin Resistance and Insulin Resistance Syndrome Insulin resistance is the physiological state in which a normal amount of insulin produces a subnormal physiological response. Lean nondiabetic subjects are two times more sensitive to insulin than obese nondiabetic subjects and obese type 2 diabetics are more insulin-resistant than obese nondiabetic subjects (26). Plasma insulin levels increase as a result of a deficient peripheral tissue response to insulin-mediated glucose metabolism. Insulin resistance occurs early in pre-type 2 diabetics and a majority, but not all, of insulin-resistant individuals will progress to overt type 2 diabetes. Insulin resistance is

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most closely associated with acquired or lifestyle factors as obesity, aging, pregnancy, and physical inactivity (27), with currently identified gene mutations accounting for only a small minority of insulin resistance cases. In addition to being one of the major pathophysiological abnormalities in type 2 diabetes, insulin resistance promotes an atherogenic lipid profile, endothelial dysfunction, increased sympathetic nervous system activity, impaired fibrinolysis, and a hypercoagulable state (28). The Helsinki Policemen Study (29) demonstrated that insulin resistance alone was a predictor of CHD. Insulin resistance syndrome, also referred to as the metabolic syndrome, is a clinical syndrome defined by the presence of three or more of the following five abnormalities (12): (i) abdominal obesity (female waist circumference greater than 35 inches and male waist circumference greater than 40 inches); (ii) triglycerides greater than 150 mg/dL; (iii) high-density lipoproteins (HDL) less than or equal to 40 mg/dL in men or less than or equal to 50 mg/dL in women; (iv) hypertension (blood pressure 130/85 mmHg); and (v) hyperglycemia (fasting blood glucose 110 mg/dL). These parameters are often observed in the obese, prediabetic individual. The overall prevalence of the metabolic syndrome in the United States is 22%, with an age-dependent increase (6.7%, 43.5%, and 42.0% for age groups 20 to 29, 60 to 69, and >70 years, respectively) (30). The World Health Organization and the International Diabetes Federation have proposed slightly different criteria for the metabolic syndrome (31,32), and the European Group for the Study of Insulin Resistance has suggested that a more appropriate name would be the “insulin resistance syndrome” (33). Patients with the metabolic syndrome are at significantly increased risk of coronary artery disease as demonstrated by the Kuopio Ischemic Heart Disease Risk Factor Study (34). In this Finnish, population-based, prospective cohort study, 1209 men without preexisting coronary disease or diabetes were tested for metabolic syndrome and followed for a mean of 11.4 years. Men with metabolic syndrome were 2.9 (95% CI 1.2–7.2) to 4.2 (95% CI 1.6–10.8) times more likely to die of ischemic heart disease after adjustment for conventional cardiac risk factors. Although there is ongoing debate as to what precisely constitutes the metabolic syndrome and whether it is in fact a true syndrome, the current obesity epidemic in the United States has thrust it into the forefront of public health efforts to reduce the incidence of type 2 diabetes and CHD (35). Numerous clinical studies have produced compelling data regarding the importance of weight loss, exercise, and a healthy diet. In both the Diabetes Prevention Program (36) and the Finnish Diabetes Prevention Study (37), behavior modification interventions in patients with impaired glucose tolerance produced an identical 58% reduction in the progression to type 2 diabetes. A secondary analysis of the Diabetes Prevention Program showed that over 3.2 years the prevalence of the metabolic syndrome decreased from 51% to 43% in the lifestyle intervention group and increased from 55% to 61% in the usual care group, demonstrating that lifestyle modification is effective in delaying or preventing the development of both the metabolic syndrome and type 2 diabetes (38). CARDIOVASCULAR COMPLICATIONS OF DIABETES MELLITUS Pathophysiological Changes The complications of diabetes mellitus have traditionally been divided into two major categories: (1) microvascular complications including retinopathy, neuropathy, and nephropathy and (2) macrovascular complications including coronary artery disease,

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cerebrovascular disease, and peripheral arterial disease (PAD). The microvascular complications are unique to diabetes, whereas the macrovascular findings are similar in patients with and without diabetes. Microvascular Pathophysiology Chronic hyperglycemia is a major initiator of microvascular complications. Two studies, the Diabetes Control and Complications Trial (DCCT) and United Kingdom Prospective Diabetes Study (UKPDS), demonstrated that aggressive control of hyperglycemia reduces the onset or progression of nephropathy, retinopathy, and neuropathy associated with type 1 and type 2 diabetes (39,40). Cardiac microvascular dysfunction is manifested by impaired autoregulation of coronary blood flow and vascular tone in the absence of significant epicardial coronary artery disease, with a resultant reduction of maximal coronary blood flow and coronary flow reserve (41,42). Although no occlusive lesions in the diabetic coronary microcirculation have been demonstrated, other structural changes (medial hypertrophy, perivascular fibrosis, and intimal hypertrophy) have been documented (43). These histopathological changes in conjunction with impaired endothelial function at the microvascular level may explain the higher frequency of silent ischemia, exercise thallium defects, myocardial fibrosis, and left ventricular dysfunction in diabetics in the absence of occlusive epicardial coronary disease (44). Macrovascular Pathophysiology Diabetes mellitus accelerates atherosclerosis via chronic hyperglycemia, insulin resistance, and dyslipidemia. Both hyperglycemia and insulin resistance impair endotheliumdependent vasodilation by decreasing the nitric oxide formation (45). Increased levels of endothelin-1 in diabetics stimulate vasoconstriction, induce vascular smooth muscle hypertrophy, and activate the renin-angiotensin system (46). Diabetes promotes the accumulation of foam cells in the subendothelial space by increasing the production of leukocyte adhesion molecules and proinflammatory mediators (47). Plaque instability and rupture is increased in diabetics as a result of decreased synthesis and increased breakdown of the collagen that plays a critical role in reinforcing the fibrous cap of vulnerable plaques (48,49). In addition to the atherosclerotic effects of diabetes upon the arterial wall, the hematologic system is adversely affected. Diabetes promotes platelet activation by increasing platelet-surface expression of glycoprotein Ib, which mediates binding to the glycoprotein IIb/IIIa (GpIIb/IIIa) receptor and to the von Willebrand factor (50). Inhibitors of platelet activity, including platelet-derived nitric oxide and endothelial prostacyclin, are decreased in diabetes. Diabetes also increases coagulation activity by stimulating production of procoagulants such as tissue factor and by reducing levels of anticoagulants such as protein C and antithrombin III (51,52). Furthermore, decreased levels of plasminogen activator type 1 in diabetics result in impaired fibrinolysis (53). Clinical Consequences of Diabetes Mellitus Coronary Heart Disease The Framingham Study demonstrated that diabetes is a powerful predictor of CHD with an average twofold increase in risk for men and threefold for women (54). The elderly diabetic patient is at particularly high risk for coronary heart disease; in one study 44% of

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octogenarians with diabetes were found to have CHD (16). Diabetic women are also at increased risk for CHD, experiencing a CHD mortality rate similar to that of diabetic men, and a five- to sevenfold higher rate of CHD mortality compared with age-matched, nondiabetic women (55). These and other data suggest that diabetes may abrogate the socalled female advantage for CHD mortality, thus accounting for the higher CHD rates in premenopausal diabetic women (14,56). The excess mortality from CHD in diabetic women compared with diabetic men increases with advancing age. In the MONICA study, the attack rate for acute MI increased almost 10-fold for diabetic women aged 55 to 64 years compared with those aged 45 to 54 years, whereas the increase was only twofold in male subjects (13). More recently, a population-based autopsy series from the Mayo Clinic characterized coronary atherosclerosis in 293 diabetic and 1736 nondiabetic subjects with a mean age of 73 and 75 years, respectively, and a male-to-female gender ratio of approximately 1:1. The study demonstrated that among diabetic decedents without clinical CHD, almost 75% had high-grade coronary atherosclerosis and more than half had multivessel disease. Nondiabetic women had less atherosclerosis than men, but the female advantage was lost with diabetes regardless of age. In addition, diabetic decedents without clinical CHD had a prevalence of high-grade atherosclerosis similar to that observed in nondiabetic decedents with clinical CHD (57). Although diabetes leads to increased incidence of CHD and MI, controversy continues as to whether the distribution of coronary artery disease is different in diabetics than in nondiabetic patients. Some investigators have found that diabetics referred for intervention (surgical or percutaneous) have diffusely diseased, frequently inoperable vessels (58). Others have reported a higher incidence of left main coronary artery disease (13% vs. 6% in diabetics vs. nondiabetics), while still other investigators have found more triple-vessel disease in diabetics (43% vs. 25%) than in nondiabetics (59). However, other studies have found no difference in the distribution of coronary artery disease in diabetics compared with nondiabetic populations (60,61). Diabetes is associated with an increased prevalence of silent ischemia and unrecognized MI. In a study from Marseilles, France, the prevalence of silent ischemia was found to be approximately 30% in type 2 diabetic men with established CHD, while the prevalence in nondiabetic patients was 1% to 4% (62). Similarly, in a study by Naka, diabetics had a 2.2 times higher prevalence of silent myocardial ischemia compared with nondiabetic controls with established CHD (63). Both the Framingham (64) and World Health Organization (65) epidemiological studies have reported an increased incidence of asymptomatic MI in the elderly. Aronow and Epstein demonstrated silent myocardial ischemia by Holter monitoring in 34% of an elderly group of patients residing in a home for the aged (66). It is, therefore, likely that the elderly diabetic patient is particularly prone to harbor asymptomatic CHD. More recently DeLuca et al. conducted a retrospective chart review of 287 patients with diabetes (71% men; mean age 83
8 years) and 292 age- and gender-matched patients without diabetes (67). Of the diabetic patients without prior history of MI, 18% were diagnosed as having had a prior unrecognized infarct compared with 7% of those without diabetes (p < 0.001). Similarly, silent myocardial ischemia was diagnosed in 33% of those with diabetes compared with 15% of those without (p < 0.001). Thus, even at an advanced age, diabetic patients have a higher prevalence of unrecognized MI and silent myocardial ischemia than patients without diabetes. The mechanisms responsible for silent ischemia in diabetes are not well understood but may include altered pain threshold, autonomic neuropathy leading to sympathetic denervation, higher production of b endorphins, and other factors (68–70).

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There is currently no consensus as to whether a broad-based screening program for silent ischemia should be implemented in patients with diabetes. There are no convincing published data showing that a prospectively applied screening program improves outcomes in asymptomatic diabetic patients (71). However, there are certain attributes that increase the likelihood of silent ischemia being present and, thus, make screening more productive. In addition to advanced age, male gender, poorly controlled type 2 diabetes (elevated hemoglobin A1c), and the presence of retinopathy have been shown to correlate well with the presence of silent ischemia (72,73). Patients with two or more of these characteristics are reasonable candidates for screening for silent ischemia. Acute Coronary Syndromes MI rates are increased among diabetics of all ages (74). For example, in a populationbased study by Haffner (75), the seven-year incidence of the first MI was 20% for diabetics but only 3.5% for nondiabetics. Prior history of MI increased the rate of recurrent MI and cardiovascular death in both groups (45% in diabetics and 18.8% in nondiabetics). Most importantly, in the absence of established CHD, diabetics experienced CHD morbidity and mortality at a rate equal to that of nondiabetic individuals with established CHD (20% vs. 18.8%, respectively). As a result, the NCEP now classifies diabetes as a CHD risk equivalent requiring aggressive intervention (12). Diabetes worsens short- and long-term outcomes following acute MI, especially in women. The Framingham Study determined that the overall risk of cardiac mortality was two to four times higher in diabetics than in nondiabetics. Another study described onemonth post-MI mortality rates of 14.4% in diabetic men and 21.7% in diabetic women compared with mortality rates of 8.8% and 7.8% in nondiabetic men and women, respectively. The subsequent one-year mortality of survivors was 9.6% for diabetic men and 10.7% for diabetic women compared with 5.0% and 2.5% for nondiabetic men and women, respectively (76). Diabetic patients had a 1.36 RR of death compared with nondiabetic patients in the SHOCK study, a trial of revascularization in MIs complicated by cardiogenic shock (77). In the GISSI-2 fibrinolytic therapy trial, the age-adjusted RR for mortality in diabetics was 1.4 for men and 1.9 for women (78). Diabetes also appears to worsen the prognosis of unstable angina. In the six-nation Organization for the Advancement of Structured Information Standards (OASIS) registry of unstable angina and non-Q-wave MI, diabetes independently increased the risk of death by 57% (79). Fava et al. evaluated a group of 166 type 2 diabetics with unstable angina and compared them with 162 nondiabetic subjects. Diabetic patients experienced a greater than threefold increase in mortality at three months (8.6% vs. 2.5%) that was maintained at one-year (80). The pathophysiological explanation for the poorer prognosis among diabetic patients is not entirely clear. Diabetes is associated with complicated metabolic changes and alterations in coagulation parameters that may predispose to poorer outcome (81). Diabetic patients tend to have fewer collateral vessels compared with nondiabetics and may have more diffuse coronary disease (82). The poorer diabetic outcomes may also be partially explained by the observation that anterior infarction appears be more common than inferior infarction. In one study involving 54 diabetic patients who had sustained an infarct compared with 270 nondiabetic MI patients, the incidence of anterior infarction was 43% in the diabetic group versus 13% in the comparison group (83). In a retrospective review of 147 patients with type 2 diabetes suffering a first MI in the drug and alcohol registry of treatment (DARTS), 37% of men had an anterior wall MI and 22% an inferior MI. Among women with type 2 diabetes this trend was reversed: 30% suffered

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an inferior and 22% an anterior MI (84). Thus, it is not clear whether diabetes predisposes preferentially to anterior MI. Stroke The Framingham Study and others have demonstrated that the risk of stroke is increased 1.5 to 4 times for diabetic patients (85). Four case-control studies and five prospective observational cohort studies have also established that insulin resistance alone is associated with a 60% to 160% increased risk for stroke in nondiabetic patients (86). The risk of stroke is particularly increased in younger diabetic patients. In a study by Rohr et al. (87) involving 296 patients between the ages of 18 and 44, diabetes increased the odds ratio for stroke from a low of 3.3 for African-American women to a high of 23.1 for Caucasian men. In an Australian epidemiological study of stroke patients younger than 55 years, diabetes increased the risk of stroke over 10-fold, albeit with a wide confidence interval (odds ratio 11.6, 95% CI 1.2–115.2) (88). Similar to post-MI prognosis, diabetes is also associated with a poorer prognosis after stroke. Diabetes increases the rate of stroke-related dementia by more than threefold (89). Diabetes also doubles the risk of stroke recurrence and increases stroke-related mortality (90,91). Poorer glycemic control also elevates stroke risk. In the Multiple Risk Factor Intervention Trial (MRFIT) of 347,978 men, those taking diabetes medications were three times more likely to incur a stroke (92). Several clinical trials suggest that reducing insulin resistance and improving glycemic control may prevent cerebrovascular atherosclerosis and stroke. In 1998, the UKPDS group concluded that metformin was effective in preventing stroke based on a comparison of metformin therapy (n ¼ 342) versus insulin or sulfonylurea therapy (n ¼ 951). The metformin group not only achieved better glycemic control compared with the insulin/sulfonylurea group (hemoglobin Alc of 7.4% vs. 8.0%, respectively) but also achieved a lower stroke rate [12 stroke events in the metformin group (3.3 events/1000 patient-years) vs. 60 stroke events in the sulfonylurea/insulin group (6.2 events/1000 patient-years)] (40). Two other studies demonstrated that thiazolidinediones, compared with sulfonylurea therapy, are more effective in preventing carotid atherosclerosis in diabetic patients (93,94). Congestive Heart Failure and Left Ventricular Dysfunction The importance of diabetes as a risk factor for congestive heart failure (CHF) was first established in the Framingham Heart Study. Among participants between the ages of 45 to 75 years, the frequency of CHF was increased fivefold for diabetic women and 2.4-fold for diabetic men (95). Although the etiology for CHF in diabetics is often multifactorial (concomitant hypertension, ischemic heart disease, and/or microvascular disease), in the Framingham study, diabetes was a risk factor for CHF independent of coexisting hypertension or coronary artery disease. Diabetes is observed in approximately 15% to 25% of heart failure patients in large clinical trials, and up to 30% of hospitalized heart failure patients have diabetes as a comorbid condition (96,97). In the large Assessment of Treatment with Lisinopril and Survival (ATLAS) and Studies of Left Ventricular Dysfunction (SOLVD) heart failure mortality trials (98,99) involving patients with systolic dysfunction, diabetes was identified as an independent predictor of death. In the SOLVD study diabetes was the third most important factor in predicting worsening heart failure after age and ejection fraction.

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In a study of 9591 individuals with type 2 diabetes, independent risk factors for CHF included advanced age, diabetes duration, insulin use, ischemic heart disease, and elevated serum creatinine (100). These findings are supported by a recent populationbased study of elderly patients with a mean age of 78.6 years, which concluded that diabetes is an independent risk factor for CHF and the risk of CHF increases with diabetes severity (101). Although ischemic heart disease and hypertension contribute to the increased prevalence of CHF in diabetics, some diabetic patients develop heart failure in the absence of these conditions. Such patients with nonischemic diabetic cardiomyopathy present with heart failure associated with systolic and/or diastolic ventricular dysfunction (102). The histopathological changes observed in diabetic cardiomyopathy are usually indistinguishable from those of other nonischemic cardiomyopathies. Several mechanisms may contribute to the development of diabetic cardiomyopathy. Autonomic neuropathy manifested by either depletion of myocardial catecholamine stores (103) or impaired ventricular response to exercise due to sympathetic nervous system impairment (104) may play a role. A defect in glucose transporter (GLUT)4 receptor translocation to the cell surface in diabetic patients may interfere with myocardial energy metabolism (105). In addition, decreased insulin levels in type 1 diabetics and decreased insulin sensitivity in type 2 diabetics may reduce myocyte uptake of glucose via the GLUT4 receptor, which is insulin responsive (106). The prevalence of left ventricular diastolic dysfunction is increased in the diabetic population, ranging from 27% to 70%. In large population-based studies, including the Strong Heart Study (107) and the Cardiovascular Health Study (108), relative to nondiabetics, echocardiograms of diabetic patients with no clinical history of heart failure demonstrated higher left ventricular mass, increased wall thickness, and greater arterial stiffness, all of which predispose diabetics to diastolic dysfunction. Diabetic patients may also have reduced systolic function at rest, lower ejection fractions with exercise (109), and reduced exercise tolerance despite well-controlled type 2 diabetes and hypertension (110). Functional impairments in vascular reserve in the peripheral, coronary, and cerebral circulation have also been demonstrated in diabetic patients. Reduced coronary flow reserve and impaired vasomotor reactivity have been observed in patients with diabetes and angiographically normal coronary arteries, suggesting the presence of early endothelial dysfunction (111,112). These alterations in functional, rather that structural, coronary flow may account for the benefits of tight glycemic control and endothelial function-enhancing angiotensin-converting enzyme (ACE) inhibitors in the diabetic heart failure population. The importance of glycemic control in heart failure is illustrated by a large population-based study of 48,858 type 2 diabetic patients with no known history of heart failure who were followed for a mean of 2.2 years (113). After adjusting for multiple factors including age, sex, hypertension, alcohol consumption, duration of diabetes, and use of b blockers or ACE inhibitors, each 1% increase in glycosylated hemoglobin was associated with an 8% increased risk of heart failure. Conversely, after controlling for hypertension, age, and gender, heart failure appears to be a risk factor for the development of diabetes mellitus (114). During three-year follow-up of an elderly patient population, Scherer et al. demonstrated that the incidence of new-onset diabetes was 29% in heart failure patients, compared with 18% in subjects without heart failure (115). Autonomic Nervous System Dysfunction Diabetic autonomic neuropathy affects multiple organ systems including the gastrointestinal, neuroendocrine, genitourinary, and ocular systems. In a study of 120 asymptomatic

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diabetic patients with no known history of coronary artery disease and normal 12-lead ECG, cardiovascular autonomic neuropathy (CAN) was present in 39% of the patients (116). In this study, the presence of CAN was also associated with an increased risk of subsequent major cardiac events, (8 out of 33 patients with CAN vs. 3 out of 42 in those without CAN; p ¼ 0.04). This finding may be explained by the observation that the parasympathetic system is affected earlier than the sympathetic system with a resultant relative increase in the sympathetic tone accompanied by elevated blood pressure and increased vasoconstriction. Diabetic patients with autonomic nervous system dysfunction frequently present with orthostatic hypotension (fall in systolic blood pressure >20 mmHg lasting 3 min with a position change from supine to upright) and decreased exercise tolerance. Central and peripheral sympathetic denervation results in decreased splanchnic and peripheral vascular-bed vasoconstriction with resultant orthostatic hypotension. Diabetic postural hypotension can vary on a daily basis and may be exacerbated by insulin therapy and after meals (117). Decreased exercise tolerance is due to impaired sympathetic output with a resultant decrease in cardiac output. In advanced autonomic nervous system dysfunction, cardiac denervation can result in a fixed heart rate of 80 to 90 beats per minute (118). Sympathetic tone may be increased during the day and parasympathetic tone decreased at night, potentially increasing the risk for nocturnal arrhythmias (119). Cardiac autonomic function can be assessed indirectly by cardiovascular reflex testing or directly by scintigraphic imaging. Cardiovascular reflex testing includes evaluation of both the sympathetic and parasympathetic systems by assessing heart rate variability with deep breathing, blood pressure response to handgrip and fall in systolic blood pressure with position changes (120). Scintigraphic imaging with metaiodobenzylguanidine or 11C-hydroxyephedrine (both radiolabeled norepinephrine analogs that undergo uptake by the cardiac sympathetic nerve terminals) is more sensitive than reflex testing but not widely available. Treatment of cardiovascular autonomic dysfunction includes lifestyle modifications, discontinuation of certain medications, and pharmacological therapy. Lifestyle modifications include a high-salt diet, small meals, avoiding alcohol and excessive heat, a 308 head-up tilt while sleeping, gradual changes in position, lower extremity compression stockings, and isometric exercises while upright (handgrip or “crossing leg” exercises). Potentially aggravating medications include diuretics, antihypertensives, and antidepressants. Pharmacological therapy includes fludrocortisone (mineralocorticoid), desmopressin (decreases vasopressin release), midodrine (a-receptor agonist), pindolol (b blocker with intrinsic sympathomimetic activity), and octreotide (somatostatin analog). Elderly diabetic patients with orthostatic hypotension may be particularly difficult to treat since many such patients have comorbid conditions that require the administration of antihypertensive drugs and/or diuretics. Peripheral Arterial Disease Diabetic patients have a two- to fourfold increase in the incidence of PAD (121). In one study, patients with normal glucose tolerance had a 7% prevalence of abnormal anklebrachial indices, while patients on multiple diabetic medications had a 20.9% prevalence of abnormal indices (122). Unlike microvascular disease, which is unique to diabetes, macrovascular disease manifesting as PAD is generally similar in diabetics and nondiabetics and is the result of accelerated atherosclerosis. However, some clinical differences exist in diabetic PAD: (i) The disease is more likely to involve the infrapopliteal arteries of the lower extremities (123); (ii) claudication is more common in

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diabetics (3.5-fold risk in men and 8.6-fold risk in women) (124,125); and (iii) amputation is much more frequent in diabetics, especially in older diabetics. The 12.7 (95% CI, 10.9–14.9) RR of lower extremity amputation in diabetic versus nondiabetic patients increases to 23.5 (95% CI, 19.3–29.1) in diabetics 65 to 74 years old (126). Both the incidence and extent of the disease are directly associated with the duration and severity of diabetes. MANAGEMENT OF CARDIOVASCULAR DISEASE IN PATIENTS WITH DIABETES MELLITUS Acute Coronary Syndromes Few studies have addressed specifically the impact of modern medical therapies for acute coronary syndromes (ACS) in the diabetic population. Subgroup analyses, however, of several clinical trials suggest a generally consistent beneficial effect of modern therapies in diabetic patients. The management of ACS is similar for elderly patients with and without diabetes with few exceptions, as noted below. Four major issues will be considered here: (i) optimal reperfusion therapy for ST-elevation MI (STEMI); (ii) early invasive versus early conservative management of unstable angina and non–ST-elevation MI (UA/NSTEMI); (iii) adjunctive pharmacotherapy and its applicability to the elderly diabetic patient with ACS; and (iv) glycemic control in patients with ACS. Reperfusion Therapy for STEMI Thrombolytic therapy. Thrombolytic (TL) therapy for STEMI has been shown to be equally or more beneficial in the diabetic patient compared with the nondiabetic. The Fibrinolytic Therapy Trialists (FTT) overview found a statistically greater mortality benefit in the diabetic group: 37 lives saved per 1000 patients treated compared with 15 lives saved per 1000 treated patients among nondiabetics (127). Similarly, an angiographic analysis that included 310 patients with diabetes in a Global Utilization of Streptokinase (GUSTO) I substudy demonstrated comparable infarct-related artery patency at 90 minutes after TL therapy in patients with and without diabetes (128). Concerns about possible increased ocular hemorrhagic complications because of underlying diabetic retinopathy have not been substantiated (129). The beneficial effects of TL in the very elderly (>75 years of age) are uncertain. The original FTT overview showed no statistically significant survival benefit in patients over the age of 75 years, possibly due to an increased incidence of hemorrhagic stroke. However, reanalysis of the FTT data showed that among patients treated within six hours of the onset of STEMI, mortality was significantly reduced in patients over 75 years of age, and the absolute benefit was similar to that seen in patients 55 to 74 years of age (130). Conversely, two more recent population-based analyses suggest that short-term mortality from STEMI is not reduced and may even be increased in patients over 75 years who receive TL therapy (131,132). Thus, the use of this form of reperfusion therapy in very elderly patients with and without diabetes remains controversial. For patients up to age 75, however, there is clear evidence from multiple randomized controlled trials that TL therapy affords a significant survival benefit. Primary percutaneous coronary intervention. Acute success rates with primary percutaneous coronary intervention (PPCI) are comparable in the presence or absence of diabetes, although the restenosis and long-term mortality rates are higher in diabetic patients (133,134). Despite the well-known limitations of PPCI (lack of widespread

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availability and treatment delays), accumulating evidence suggests that this form of reperfusion therapy may well be superior to TL in improving clinical outcomes if performed expeditiously by experienced operators (135). Data comparing TL with PPCI in elderly diabetic patients are limited. A recent observational study comparing early and late outcomes of PPCI and TL therapy of diabetic patients with STEMI concluded that PPCI was associated with reduced early and late adverse outcomes when compared with TL therapy (136). However, mortality was similar in both groups. In this study over onethird of the patients were 65 years or older. The advent of stents has bolstered the role of PPCI as the reperfusion treatment of choice in acute STEMI. In the Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) trial, routine stent implantation in diabetic patients with an acute STEMI significantly reduced restenosis and improved survival free from subsequent target vessel revascularization. Despite these improved outcomes with stenting in patients with diabetes, one-year mortality was significantly higher in diabetic patients who received stents compared with nondiabetics (8.2% vs. 3.6%; p ¼ 0.005) (137). On the basis of available data, it is reasonable to conclude that PPCI is preferable to TL in the elderly diabetic patient with STEMI, including those over the age of 75. Management of UA/NSTEMI Beginning with the Thrombolysis in MI (TIMI) III study of early invasive versus early conservative management of UA, subgroup analyses of several randomized controlled trials have demonstrated a consistent, modest benefit of early invasive therapy in elderly patients (aged > 65 years) and in diabetics. In the Fast Revascularization During Instability in Coronary Artery Disease (FRISC) II trial (138), reduction in the composite endpoint of death and nonfatal MI among those assigned to the early invasive group resulted entirely from the benefit realized by the subgroup over age 65. The five-year outcomes of the FRISC II trial showed sustained benefits in favor of the invasive strategy for the primary endpoint of death or nonfatal MI (19.9% in the invasive arm vs. 24.5% in the noninvasive arm). This benefit was confined to nonsmokers and male patients with two or more risk indicators (aged > 65 years, diabetes mellitus, ST-segment depression, and elevated troponin level on admission) (139). The more recent TACTICS-TIMI 18 study compared outcomes of ACS patients treated with the glycoprotein IIb/IIIa (GP IIb/IIIa) inhibitor tirofiban and assigned to either an early invasive strategy and revascularization if clinically indicated or to a more conservative strategy in which cardiac catheterization was undertaken only if the patient demonstrated spontaneous or provoked ischemia (140). Although there was no clear survival benefit, the results demonstrated a 3.1% absolute and 33% RR reduction for the combined endpoint of death, nonfatal MI, and rehospitalization for ACS at six months in patients assigned to an early invasive strategy. Subgroup analysis demonstrated that patients over the age of 65 years had a 4.6% absolute reduction in the combined endpoint compared with a 2.9% reduction for patients under the age of 65. Similarly, diabetic patients realized a 7.6% absolute reduction compared with 2.2% for nondiabetic patients. On the basis of these and other trials, an early invasive strategy is considered to be the preferred method of managing “high-risk” patients with UA/NSTEMI. Since both advancing age and diabetes increase the risk of adverse outcomes, it is reasonable to conclude that an early invasive strategy is appropriate in the elderly diabetic patient with UA/NSTEMI. An important limitation of these studies, however, is that very few diabetic patients over the age of 80 were enrolled (141).

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Adjunctive Therapies in ACS In almost all respects, the adjunctive therapy of ACS is the same for patients with and without diabetes mellitus (142). However, specific contraindications and risks must be recognized as discussed below. Aspirin. The beneficial effects of aspirin in ACS have been conclusively demonstrated in many studies. In the International Study of Infarct Survival ISIS-2 study, aspirin was shown to be as efficacious in older as in younger patients with MI (143). Several studies have shown that patients with either type 1 or type 2 diabetes mellitus have a prothrombotic state including enhanced platelet aggregation in response to various stimuli (144,145), and that agents that inhibit platelet aggregation in vivo consistently reduce the incidence of thrombotic events. In a meta-analysis of 145 prospective controlled trials of antiplatelet therapy after an MI, stroke, or transient ischemic attack reported by the Antiplatelet Trialists (146), antiplatelet therapy was associated with a reduction of about 25% in vascular events, and diabetic patients had risk reductions similar to nondiabetic individuals. Consequently, aspirin in doses of 162 to 325 mg should be administered to all patients with ACS and should be continued indefinitely if there are no major contraindications (e.g., bleeding peptic ulcer). Other antiplatelet therapy. Platelet aggregability is enhanced in patients with diabetes mellitus. Several studies have shown that GP IIb/IIIa inhibitors, when added to aspirin, improve outcomes in high-risk patients with UA/NSTEMI, especially those undergoing percutaneous coronary intervention (PCI). A review of the results of four abciximab trials (147) reveals that this agent is safe and effective in patients over the age of 70, although the net benefit declines slightly with increasing age. Tirofiban and eptifibatide have also been shown to be effective agents in this setting. In a meta-analysis by Roffi et al. of six large randomized ACS trials involving 6458 patients with and 23,072 patients without diabetes and in which immediate PCI was not mandated, benefits from GP IIb/IIIa inhibitors were seen mainly among patients with diabetes, in whom 30-day mortality was reduced by 26%, from 6.2% to 4.6% (p ¼ 0.007). Even more striking was the benefit of GP IIb/IIIa inhibitors among diabetic patients undergoing PCI. In this subgroup, 30-day mortality was reduced by 70%, from 4.0% to 1.2% (148). It is not clear whether this preferential benefit in diabetics is related to diabetes-associated conditions such as increased platelet activation and accentuated inflammatory responses, or is because of the more diffuse atherosclerotic process of diabetes. Nevertheless, routine use of these agents is recommended for moderate- and high-risk diabetic patients with ACS. Clopidogrel was shown in the Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events (CURE) trial to improve long-term outcomes when administered for three to nine months to patients with UA/NSTEMI who did not undergo PCI (149). Improved outcomes were demonstrated in patients over the age of 65 years and in patients with diabetes mellitus. However, diabetic patients derived only a modest benefit from combined aspirin/clopidogrel therapy at 3 to 12 months, with a composite death, an MI, or a stroke rate of 14.2% versus 16.7% (p ¼ ns). In patients undergoing PCI (PCI-CURE study), combined aspirin/clopidogrel therapy conferred a slightly lower benefit in diabetic patients (absolute risk reduction 3.6% compared with 3.8% in nondiabetics) (150). Similar results were obtained in the more recent Clopidogrel for the Reduction of Events During Observation (CREDO) trial in which the benefit from pretreatment/sustained clopidogrel therapy in 560 diabetic patients was again modest compared with that observed among the 1556 nondiabetics (RR reduction 11% and 33%, respectively for the

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primary composite endpoint of death, MI, and stroke at one year) (151). Nevertheless, sufficient benefit is obtained from combined aspirin/clopidogrel therapy in diabetic ACS patients to suggest that it should be administered to all such patients unless contraindicated. The use of triple antiplatelet therapy (aspirin-clopidogrel-GP IIb/IIIa inhibitors) in elderly diabetic ACS patients has raised concerns because of the increased risk of bleeding. Despite these concerns, results obtained in diabetic patients undergoing PCI and receiving triple antiplatelet therapy in the TARGET (152) and other trials suggest that such therapy is probably warranted in elderly diabetic patients with ACS unless major contraindications exist. Data for patients 80 years and older is sparse due to enrollment bias in almost all studies (141). Antithrombotic therapy. Intravenous unfractionated or low-molecular-weight heparin (LMWH) should be administered to all patients with ACS regardless of age and diabetic status unless there are major contraindications (e.g., intracranial bleed). Recent studies have shown that LMWH is superior to unfractionated heparin in patients with UA/NSTEMI, especially in elderly patients (153,154). Concerns regarding excess bleeding when patients receiving LMWH undergo an invasive procedure have not been substantiated. b-Adrenoreceptor blockers. b Blockers have been found to be effective in improving outcomes when used for ACS in patients with diabetes. Several studies have consistently demonstrated an average twofold greater reduction in the RR of mortality as a result of b-blocker therapy after MI in patients with diabetes compared with those without diabetes. Despite these findings, diabetics with coronary artery disease are undertreated with b-blocker drugs. Reviewing a large cohort of patients from the National Cooperative Cardiovascular Project, Chen et al. reported that even after adjusting for demographics and clinical factors, patients with diabetes were less likely to receive b blockers at discharge following acute MI, with odds ratios for insulin-treated and non-insulin-treated diabetics of 0.88 and 0.93, respectively (155). In the same study, b blockers were found to be associated with lower one-year mortality for insulin-treated diabetics, non-insulintreated diabetics, and nondiabetics (hazard ratios 0.87, 0.77, 0.87, respectively). Furthermore, b-blocker therapy was not significantly associated with increased sixmonth readmission rates for diabetic complications. The authors concluded that b-blocker therapy following acute MI is associated with similar reductions in one-year mortality rates for elderly diabetic and nondiabetic patients without increasing the risk of diabetic complications. Subgroup analysis of several large b-blocker trials has shown a 30% to 58% reduction in post-MI mortality in diabetic patients treated with timolol (156) or metoprolol (157). In the more recent Effect of Carvedilol on Outcome after MI in Patients with Left Ventricular Dysfunction (CAPRICORN) trial, all-cause mortality was reduced from 15% in the placebo group to 12% in the carvedilol group (RR reduction 23%; p ¼ 0.031) (158). The benefit derived from carvedilol was equal in patients under or over age 70. Patients with diabetes also derived benefit, although to a lesser extent than nondiabetics. On the basis of these and other studies, b blockers should be used in all elderly diabetic patients with ACS in the absence of major contraindications (severe bradycardia with heart rate <45–50 beats/min, systolic blood pressure <100 mmHg, severe heart failure, PR interval >0.24 seconds or higher degrees of atrioventricular block, and active bronchospastic lung disease). ACE inhibitors. Early treatment with an ACE-I is recommended for patients with an anterior STEMI, left ventricular systolic dysfunction with an ejection fraction of less than

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0.4, or overt heart failure in the absence of contraindications such as hypotension, renal insufficiency, or hyperkalemia (159–161). These agents are beneficial in other forms of ACS as well, but the evidence is less compelling. Despite the generally recognized benefits of ACE-I in diabetic patients, these agents are under-prescribed because of concerns regarding azotemia, hemodynamic instability (especially if diabetes-related autonomic neuropathy is present), and hyperkalemia. However, results from multiple studies do not support these concerns. A retrospective analysis of the GISSI 3 study suggests that most, if not all, of the mortality benefit resulting from treatment with lisinopril versus placebo was found in the diabetic subgroup (162). In the CONSENSUS II study, hypotension neutralized any potential benefit of early ACE inhibition in ACS patients treated with intravenous enalaprilat, but in the diabetic subgroup, those receiving enalaprilat exhibited a significant improvement in outcomes at six months compared with placebo (163). The Heart Outcomes Prevention Evaluation (HOPE) trial investigated the effect of ramipril versus placebo in 9297 high-risk patients 55 years of age or older with evidence of vascular disease or diabetes plus one other cardiovascular risk factor and without left ventricular dysfunction or heart failure (164). Patients with diabetes constituted 38% and 39% of the treatment and placebo groups, respectively. Ramipril was found to significantly reduce the risk of MI, stroke, or death from cardiovascular causes compared to placebo. The beneficial effect of treatment with ramipril on this composite outcome was consistently observed in patients with or without diabetes mellitus and was independent of age. Thus, the HOPE trial confirms results of prior studies regarding the benefits of ACE-I in diabetic patients. Glycemic Control in ACS Hyperglycemia is associated with multiple deleterious biochemical changes including increased activation of both inflammatory and thrombotic pathways, increased oxidative stress, and microcirculatory effects including reduced vasodilation in response to ischemia, decreased response to vasodilators, reduced coronary collateral blood flow, and reduced nitric oxide synthesis (165,166). These changes adversely impact outcomes in ACS. Conversely, insulin has anti-inflammatory and antithrombotic activity, and acts as a vasodilator and inhibits platelet activation (167). One would, therefore, expect that in diabetic patients with ACS, tight glycemic control and/or insulin administration might improve outcomes. Twenty nine trials and meta-analyses investigating the role of insulin treatment [administered either for tight glycemic control or as a component of glucose-insulinpotassium (GIK) regimens] in patients with ACS or undergoing cardiac surgery have been published since the year 2000 (168). Conflicting results have been reported and, in general, the trials are difficult to interpret because of heterogeneity of the study populations and the treatment regimens. Therefore, despite some studies demonstrating a modest survival benefit in diabetic patients with ACS treated with GIK (169), the overall evidence suggests that the use of GIK is probably not beneficial (168). On the other hand, substantial data support the aggressive treatment of diabetes with insulin at the time of an acute illness including ACS both in terms of improving short-term outcomes and for preventing long-term cardiovascular and microvascular complications (170–173). A recently proposed paradigm of care for managing NSTEMI, known as the “ABCDE” approach, emphasizes the importance of diabetes management (the “D” in “ABCDE”) in the setting of ACS (174). Recently, Swedish investigators reported that in diabetic patients with ACS, hyperglycemia on arrival to the hospital and hypoglycemia during hospitalization were

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both independently associated with worse adjusted all-cause mortality risk (175). The authors concluded that avoidance of both hyper- and hypoglycemia during ACS events is important, and that proper glycemic control is a major objective of ACS care. Despite the theoretical and clinical evidence pointing to the importance of glycemic control in ACS patients, management of diabetes in this setting is frequently suboptimal. A recent study found that almost one-third of 235 diabetic patients admitted with ACS did not have an assessment of HbA1c during hospitalization or at discharge, particularly older patients and those not evaluated by an endocrinologist. In addition, only 42% of patients with HbA1c levels of 7% to 9% had their diabetic medications adjusted (176). Chronic Ischemic Heart Disease The medical management of chronic ischemic heart disease and stable angina pectoris is the same for elderly patients with and without diabetes. In the absence of contraindications, all patients with stable angina should be treated with aspirin, a b blocker, an ACE inhibitor or angiotensin receptor blocker (ARB), and a statin. Additional drugs that may be indicated in selected cases include long- and short-acting nitrates, calcium channel blockers, ranolazine, and clopidogrel. There is agreement that the presence of diabetes does not require a change in the pharmacotherapy of stable angina, nor is there compelling evidence that these drugs have untoward effects in diabetics. Management of Silent Ischemia The proper management of the elderly diabetic patient with silent ischemia starts with lifestyle modification and aggressive medical therapy of the commonly associated hypertension and hyperlipidemia, as is true for all diabetics. There is evidence that agents that are used to treat symptomatic ischemia (b blockers, calcium antagonists, and nitrates) also effectively reduce or eliminate episodes of silent myocardial ischemia (177,178). However, there is no evidence that anti-ischemic medical therapy can alter the natural history of CHD in these patients. Coronary revascularization is also effective in reducing or eliminating episodes of silent ischemia. In the Asymptomatic Cardiac Ischemia Pilot (ACIP) trial, 57% of patients randomized to revascularization were free of ischemia at one year compared with 31% in the ischemia-guided strategy group (179). In the recently reported Swiss Interventional Study on Silent Ischemia Type II (SWISSI II) randomized study on the effects of PCI in patients with silent ischemia following an MI, an absolute reduction of 6.3% in major cardiac events (cardiac death, recurrent MI, and/or symptom-driven revascularization) was recorded for the PCI group compared with the anti-ischemia drug therapy group (180). It is not clear whether the results of this study can be applied to elderly diabetic patients with silent ischemia since the mean age of enrolled patients was 54.4 years in the PCI group and 56.2 years in the medical therapy group. Similarly, only 9.4% of PCI patients and 13.3% of medical therapy patients had documented diabetes. Nevertheless, the practice of referring diabetic patients with silent ischemia and high-risk noninvasive test results to coronary angiography and revascularization seems reasonable (181). Revascularization Therapy Almost 25% of the surgical and percutaneous coronary revascularization procedures performed annually in the United States are in patients with diabetes. Most of these patients have comorbid conditions that contribute to worse short- and long-term outcomes after revascularization. These comorbidities include hypertension, dyslipidemia, systolic

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and diastolic left ventricular dysfunction, PAD, cerebrovascular disease, nephropathy, and a prothrombotic state. Acute success rates of percutaneous transluminal coronary angioplasty (PTCA) are similar for patients with and without diabetes. However, the incidence of restenosis, the need for repeat revascularization, and long-term mortality after PTCA are higher in diabetic patients. Data from the National Heart, Lung, and Blood Institute (NHLBI) registry indicated that the nine-year mortality of diabetic patients after PTCA was almost double than that for nondiabetics (182). Such data have raised the possibility that coronary artery bypass graft surgery (CABG) may be advantageous in diabetic patients. The Bypass Angioplasty Revascularization Investigation (BARI) trial compared the two types of revascularization therapy in patients with two- or three-vessel disease. The overall five-year survival rates of 89.3% in the CABG group and 86.3% in the angioplasty group were not statistically different (183). However, in the subgroup of BARI patients with treated diabetes mellitus (not a prespecified subgroup), a significant difference was observed in favor of bypass surgery (survival of 76% for CABG vs. 56% for PTCA; p ¼ 0.0011) (184). Improved five-year survival in CABG patients was entirely due to reduced cardiac mortality (5.8% vs. 20.6%; p ¼ 0.0003). Improved survival with bypass surgery in treated diabetics was confirmed at seven-year follow-up of the BARI trial (185). It should be noted, however, that the survival advantage of CABG was largely confined to patients who received at least one arterial conduit. The results of the BARI trial could not be confirmed in the Emory Angioplasty versus Surgery Trial (EAST) or the Duke Cardiovascular Registry (186,187). However, a more recent analysis of the EAST data suggests that, after accounting for baseline differences between groups, there was a higher long-term mortality rate for diabetic patients treated with angioplasty compared with those undergoing CABG (188). Several possible mechanisms have been proposed for the higher mortality rate after PTCA in insulin-requiring patients with diabetes: impaired endothelial function, a prothrombotic state, increased intimal hyperplasia, and increased protein glycosylation and vascular matrix deposition. Alternatively, insulin-requiring diabetes may be a marker for more severe disease and may identify patients for whom surgery is a better option than angioplasty. A limitation of both BARI and the Duke Registry is that neither study included a significant number of patients treated with intracoronary stents or GP IIb/IIIa inhibitors. These treatment modalities have improved the outcomes of PCI in diabetics as well as in nondiabetics. Evaluation of Platelet lIb/IIIa Inhibitors for Stenting Trial (EPISTENT) was a randomized study of patients with at least one coronary artery stenosis more than 60%. Patients were randomized into three treatment groups: stenting plus standard therapy and placebo, stenting plus standard therapy and abciximab, and conventional angioplasty plus standard therapy and abciximab. First generation bare metal stents (BMS) were used in this study. Subgroup analysis centered on 491 patients with diabetes mellitus (189). In this cohort, an approximately equal number of patients were assigned to each of the treatment arms, and baseline characteristics were similar in the three groups. Endpoints were sixmonth death, MI, and target vessel revascularization. In the diabetic patient cohort, a significant reduction in the combined endpoint was noted in the group treated with the combination of stenting and abciximab. An absolute reduction of events and increased benefit for all endpoints was observed in the stent/abciximab group compared with the two other treatment groups. After multivariate analysis to adjust for some imbalance of baseline clinical and angiographic findings, the benefit of stent/abciximab in diabetics remained significant ( p ¼ 0.008). Recent studies have provided evidence that drug-eluting stents (DES) may be superior to BMS in patients with and without diabetes. Two meta-analyses of randomized,

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controlled trials concluded that DES substantially reduced restenosis and target vessel revascularization compared with BMS (190,191), although short-term mortality was not different. However, data from diabetes subgroups in randomized controlled trials indicate that the rate of restenosis in diabetics treated with DES is still significantly greater than in nondiabetics (192,193). Recently reported meta-analyses of randomized trials evaluating the safety of DES have raised new serious questions and are particularly of concern regarding the use of DES in diabetic patients. One study reported a trend of increased incidence of late (after one year) DES thrombosis compared with BMS (194). A second reported a significantly better four-year survival of diabetic patients treated with BMS (95.6%) compared with patients treated with DES (87.8%; p ¼ 0.008) (195). Therefore, it is clearly premature at this point to consider DES a viable revascularization alternative to CABG for diabetic patients with multivessel CHD (196,197). This conclusion is supported by several recent small trials that have reported results similar to the BARI trial. In the Brazilian Medicine, Angioplasty, or Surgery Study (MASS), diabetic patients (mean age 60
9 years) with multivessel CHD had better fiveyear outcomes after CABG compared with patients who underwent PCI or were treated medically (198). In another study from Israel, 518 consecutive diabetic patients (29% over the age of 70) underwent revascularization, 176 by PCI incorporating the use of Cypher stents and 342 by CABG. Left main disease, total occlusion of a coronary artery, and bifurcation lesions were more prevalent in the surgical group. During a mean follow-up of 18 months, overall mortality was not different in the two groups, but recurrent angina and repeat intervention were more common in the PCI group (199). It is noteworthy that despite the reported worsening of surgical case mix, CABG is being performed in diabetic patients with low morbidity and mortality rates that are fairly comparable with those of nondiabetics. In a retrospective report from the Bristol Royal Infirmary (200) of 5259 patients undergoing CABG, the in-hospital mortality for the diabetic cohort was 2.2% compared with 1% for nondiabetic patients. Currently, the 2005 Update of the American College of Cardiology/American Heart Association (ACC/AHA) PCI Guidelines gives a class IIb recommendation (efficacy not well established) for PCI in patients with diabetes, class III angina, and two or three vessel CHD including significant left anterior descending artery disease (201). Two ongoing trials [BARI 2D and Future Revascularization Evaluation in Diabetic Patients: Optimal Management of Multivessel Disease (FREEDOM)] should help clarify the role of PCI using modern stent deployment and appropriate antiplatelet regimens in patients with diabetes and multivessel CHD. HYPERTENSION AND DIABETES MELLITUS Patients with diabetes have an increased prevalence of hypertension (202) and, conversely, hypertensive patients have an increased incidence of impaired glucose tolerance and demonstrate increased insulin release following an oral glucose load. The results of several studies support the existence of the metabolic syndrome that includes insulin resistance and hyperinsulinemia, glucose intolerance, hypertension, obesity, elevated triglycerides, and other metabolic abnormalities (203). More than seven million people in the United States have both hypertension and diabetes, and the association between these risk factors and cardiovascular disease becomes stronger with advancing age. Epidemiological studies have demonstrated that hypertension increases the risk of atherosclerotic vascular disease in diabetics more than in nondiabetics. The Systolic Hypertension in the Elderly Program (SHEP) found almost twofold increases in the five-year rates of major cardiovascular events, coronary events, and

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strokes among diabetic patients versus nondiabetic patients in the placebo group (204). The relative treatment benefit of low-dose diuretic therapy was similar in patients with diabetes compared with nondiabetic patients, but the absolute benefit was lower in patients with diabetes. The SHEP trial results refuted the belief that diuretics, which may increase blood glucose levels, must be avoided in patients with diabetes. Similar salutary effects of thiazide treatment in diabetic patients with hypertension were seen in the Antihypertensive and LipidLowering Treatment to Prevent Heart Attack (ALLHAT) trial, in which over 35% of the patients had type 2 diabetes (205). In general, the drugs commonly used to treat hypertension (b blockers, calcium channel blockers, ACE inhibitors, and diuretics) are effective in patients with diabetes (206). Thiazide diuretics in high doses can indeed aggravate hyperglycemia, but at lower doses—which are equally effective in treating hypertension—they do not significantly increase glucose intolerance. Similarly, although b blockers may worsen insulin resistance and mask symptoms of hypoglycemia, they are generally well tolerated by patients with diabetes and are especially indicated if there is associated CHD. Systolic hypertension is especially common in the elderly because of the age-related decline in compliance of the central elastic arteries. The increase in systolic pressure, in turn, results in an increase in pulse pressure (PP). Factors other than age that promote an increase in vascular stiffness and that are associated with a widened PP include tobacco, diabetes, glucose intolerance, and hyperlipidemia (207,208). The Cardiovascular Health Study found that increased PP was associated with a 21% increased risk of cardiovascular events for each progressive standard deviation increase above the mean (209). Even though a widened PP is now recognized as a risk factor for future cardiovascular events, reduction of PP has not been an endpoint in hypertension trials, and treatment goals have centered on reduction of systolic blood pressure (210). The important relationship between diabetes and BP is underscored in the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-7) (206), which sets the target for BP control for diabetics to less than 130/80 mmHg compared with the target for the general population of less than 140/90 mmHg. In the large multicenter randomized UKPDS trial, one objective was to determine whether tight control of hypertension with either a b blocker or an ACE-I was beneficial relative to standard care (211). Patients were randomly assigned to captopril or atenolol for control of hypertension. The study concluded that both agents were equally effective in reducing blood pressure as well as the risks of microvascular endpoints. Regarding macrovascular complications of diabetes, although reductions in all-cause mortality and MI did not achieve statistical significance, there was a 44% reduction of stroke and a 56% reduction of heart failure in the tight blood pressure control group compared with the conventionally treated group. Thus, aggressive therapy of hypertension in diabetic patients is crucial, but the choice of antihypertensive agent appears to be less important unless there is a specific indication for one class of drug over another. ACE-I and ARBs have been shown to slow progression of diabetic nephropathy and may, therefore, be the preferred initial agents in the presence of microalbuminurea. Similarly, b blockers are the preferred agents in patients with angina or MI. Most elderly diabetic patients with hypertension will require more than one antihypertensive drug for optimal blood pressure control (206). LIPID DISORDERS AND DIABETES MELLITUS Patients with diabetes mellitus commonly have two lipid disorders that must be considered. The first is an elevated low-density lipoprotein (LDL) cholesterol level. This leads to atherogenesis and contributes to plaque rupture and acute coronary events. The

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second is atherogenic dyslipidemia, which is characterized by increased triglyceride levels, depressed high-density lipoprotein levels, and normal to mildly increased lowdensity liproprotein levels but increased levels of small dense (easily oxidizable) LDL particles. Both these disorders are independently associated with progressive atherosclerosis and increased incidence of cardiovascular events (212,213). The importance of controlling both of these diabetes-associated lipid disorders and the impact of such control on the macrovascular complications of diabetes have been extensively studied. In 1992, the Helsinki Heart Study suggested a trend toward decreased coronary events in 135 diabetic patients treated with gemfibrozil over a five-year period, compared with those receiving placebo (214). Because of concerns regarding the efficacy and safety of fibrate therapy, this form of treatment has not gained wide acceptance. However, the more recent Diabetes Atherosclerosis Intervention Study (DAIS) has provided support for the use of fibrates in the treatment of diabetic dyslipidemia (215). DAIS was a randomized trial designed to assess the effects of correcting lipoprotein abnormalities on coronary atherosclerosis in type 2 diabetes. Patients were assigned to micronized fenofibrate or placebo and followed for at least three years. In addition to improved lipid profiles, the fenofibrate-treated patients were shown to have significantly less angiographic progression of coronary artery disease compared with the placebo group. The study was not powered to assess clinical endpoints, but there were fewer events in the fenofibrate group than in the placebo group. Recently, attention has been focused on the fundamental role inflammatory processes play in the initiation, propagation, and complications of atherosclerosis (216), and the role of peroxisome proliferator-activated receptors alpha and gamma (PPAR-a and PPAR-g) in the control of inflammation and cardiovascular risk (217). Gemfibrozil and fenofibrate are PPAR-a agonists that significantly lower triglyceride levels while modestly raising HDL cholesterol (215). In the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study of 9795 patients with type 2 diabetes, fenofibrate therapy resulted in a nonsignificant 11% reduction in the primary endpoint of CHD death or nonfatal MI (p ¼ 0.16). However, a 25% reduction in coronary events (p ¼ 0.014) was recorded in the subgroup of patients who entered the study without prior history of CHD (218). The results of the FIELD study are confounded by unequal initiation of statins in the two groups during the study, and by the mix of low-risk primary and medium-risk secondary prevention patient cohorts. Nevertheless, the FIELD study is important because it demonstrated a generally good safety profile for combined statin-fenofibrate therapy; in addition, fenofibrate therapy was associated with unexpected benefits on microvascular endpoints (microalbuminurea and retinopathy). In the Veterans Affairs High Density Lipoprotein Intervention Trial (VAHIT), gemfibrozil reduced the risk of major cardiovascular events by 24% (p < 0.001). In this study, 25% of the subjects had diabetes and most had the characteristics of the metabolic syndrome. Furthermore, the clinical benefit of gemfibrozil exceeded that attributable to changes in the lipid profile (219); this finding suggests that the cardiovascular protection provided by fibrates may be mediated in part by the anti-inflammatory actions induced by PPAR-a activation. Although the results of the fibrate studies are inconclusive in terms of clinical outcomes, subset analysis of diabetic patients in three major secondary prevention trials comparing HMG CoA-reductase inhibitors (statins) with placebo demonstrate the importance of LDL cholesterol control in diabetics. The Scandinavian Simvastatin Survival Study (4S) showed that in a subgroup of 202 diabetic patients, simvastatin led to a significant reduction in major coronary artery disease events over a five-year follow-up period compared to placebo (220). The Cholesterol And Recurrent Events (CARE) trial enrolled 586 diabetic patients and also reported a significant reduction in major coronary

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events when pravastatin was compared with placebo (221). The Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) trial enrolled 811 patients with diabetes and reported a favorable trend in the composite endpoint of CHD death or nonfatal MI over an average follow-up of six years among patients treated with pravastatin compared with placebo (222). Similar results in diabetic patients were seen in the more recent Heart Protection Study (HPS) (223) and the Collaborative Atorvastatin in Diabetes Study (CARDS) (224). The HPS demonstrated benefits from statin therapy even in patients with baseline LDL cholesterol levels less than 100 mg/dL. Subgroup analyses from the HPS, LIPID, and 4S trials showed that older individuals derived equal or greater benefit from statin therapy than younger patients. Ezetimibe is a novel lipid-lowering agent that inhibits cholesterol absorption by a unique mechanism of action. The addition of ezetimibe to a statin has been shown to result in significant additional LDL-C lowering. The Ezetimibe Add-On to Statin for Effectiveness (EASE) trial was designed to determine the effects of combination therapy on LDL-C reduction and NCEP ATP III goal attainment in a diverse population of patients. The addition of ezetimibe to a statin regimen reduced LDL-C by 25.8% (p < 0.001) below the LDL-C level of statin monotherapy (225). More than half of the patients had metabolic syndrome or diabetes mellitus and the dual regimen was well tolerated. Thus, a combined regimen of statin-ezetimibe can be used successfully in diabetic patients who fail to achieve LDL-C goals with statin monotherapy. No information is available regarding the safety and efficacy of triple hypolipidemic therapy (e.g., statinezetimibe-fenofibrate) (226). Despite the limited information that has emerged from primary prevention trials, strong evidence from secondary and some primary prevention studies indicates a definite role for lipid-altering therapy in patients with diabetes mellitus. The 4S trial showed that simvastatin treatment had a greater effect on endpoint reduction in the subgroup with diabetes than in the nondiabetic group (220); similarly, in the HPS, simvastatin reduced major coronary events and strokes in diabetic subjects with one other risk factor but no known vascular disease to the same extent as in other high-risk subjects without diabetes (223). On the basis of currently available evidence derived from multiple prospective randomized trials, statins remain the agents of first choice for the treatment of older patients with hyperlipidemia and type 2 diabetes, with the possible addition of ezetimibe to achieve NCEP Adult Treatment Panel (ATP) III goals. Fenofibrate is a reasonable second-line agent, especially for those diabetics with atherogenic dyslipidemia (high triglycerides and low HDL levels). The precise role of combined statin-fibrate therapy for cardiovascular risk reduction in patients with type 2 diabetes is under investigation in the ongoing Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Several studies have reported an increased incidence of myopathy when gemfibrozil is added to a statin and this combination is best avoided (226). Niacin has beneficial effects on total cholesterol, LDL-C, and triglycerides; it also effectively raises HDL cholesterol levels, and in combination with low-dose statin therapy it retards the progression of CHD and reduces the occurrence of major cardiac events (227). The side effects of niacin, which include cutaneous flushing, hepatic toxicity, and induction of insulin resistance have limited its use in general clinical practice. However, the problem of flushing can be addressed with good patient education and the administration of aspirin 30 to 60 minutes before niacin intake. Serious hepatic toxicity is largely confined to the use of slow-release formulations; nevertheless careful monitoring of hepatic function is necessary in all patients taking this drug. Although niacin has been shown, in short-term trials, to induce insulin resistance, the glycemic response in patients with and without diabetes is usually minor. Thus, niacin can be used

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safely in selected patients with diabetes provided careful monitoring of the various metabolic parameters is observed (228). TREATMENT OF DIABETES MELLITUS AND GLYCEMIC CONTROL Hypoglycemic Drugs The current approach to the treatment of type 2 diabetes mellitus depends on a combination of lifestyle modifications and oral agents (229). Although there is no reason why insulin should not be implemented early in the treatment of type 2 diabetes, the requirement for subcutaneous injection and the availability of new oral medications has relegated insulin therapy to a late intervention. Smoking cessation, weight loss, increased physical activity, and restricted calorie diets are the main lifestyle changes. The two most commonly used oral agents are the sulfonylureas, which stimulate insulin secretion, and metformin, which decreases hepatic glucose production and increases insulin sensitivity. Second generation sulfonylureas (glimepiride, gliclazide) may offer a survival advantage over older agents (glyburide), particularly when used in combination with metformin (230,231). Similar to sulfonylureas, glitinides (rapaglinide, nateglinide) also increase pancreatic insulin secretion. Two newer classes of hypoglycemics are the alphaglycosidase inhibitors, which inhibit gastrointestinal absorption of carbohydrates, and the thiazolidinediones (TZDs). TZDs, including rosiglitazone and pioglitazone, enhance insulin sensitivity and decrease insulin resistance by binding to PPAR-g, a nuclear receptor involved in adipose and vascular cell differentiation (232). TZDs also decrease inflammatory mediators (233), improve endothelial-dependent vascular responses (234), decrease thrombotic potential by decreasing plasminogen activator inhibitor levels (235), improve the diabetic atherogenic profile by increasing LDL particle size (236), reduce serum CRP levels (237), and reduce carotid intimal thickness (238). In the recently reported PIOSTAT study, a prospective double-blind trial, 125 highrisk patients were randomized to pioglitazone or simvastatin plus placebo or to a combination of pioglitazone and simvastatin. At 12 weeks both pioglitazone and simvastatin significantly reduced high-sensitivity CRP and the combination regimen showed additive effect (239). Whether these pleiotropic actions of TZDs will translate into improved clinical outcomes in patients with diabetes remains under investigation. The PROspective PioglitAzone Clinical Trial In MacroVascular Events (PROactive) study (240) was a placebo-controlled trial of 5238 patients with type 2 diabetes and significant macrovascular disease at baseline who were randomized to pioglitazone or placebo. The study sought to achieve similar levels of glucose control in the two arms and attempted to reach specific hemoglobin A1c levels. The pioglitazone-treated patients had a nonsignificant 10% reduction in the primary composite endpoint of all-cause mortality, nonfatal MI, stroke, ACS, coronary or lower extremity revascularization, or amputation above the ankle (p ¼ 0.095). However, pioglitazone significantly reduced the secondary endpoint, a composite of all-cause mortality, nonfatal MI, and stroke (RR 16%; p ¼ 0.027). A subsequent analysis of a subgroup of high-risk patients with prior MI (241) found that pioglitazone significantly reduced the incidence of fatal and nonfatal MI (absolute reduction 1.9%; p ¼ 0.045) and of ACS (absolute reduction 1.8%; p ¼ 0.035). However, the incidence of heart failure requiring hospitalization was 7.5% in the pioglitazone group and 5.2% in the placebo group. In the A Diabetes Outcome Progression Trial (ADOPT) study, rosiglitazone monotherapy maintained long-term glycemic control in newly diagnosed type 2 diabetics

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better than either metformin or glyburide monotherapy (242). However, glyburide was associated with a lower risk of cardiovascular events (mainly heart failure) than rosiglitazone (p < 0.05) or metformin, while rosiglitazone was associated with more weight gain and edema than either metformin or glyburide. A recent meta-analysis of 42 randomized controlled trials in which rosiglitazone was compared with either placebo or another hypoglycemic drug has raised additional serious concerns (243). In this analysis, rosiglitazone was associated with a significant increase in the risk of MI ( p ¼ 0.03) and a trend toward an increase in the risk of death from cardiovascular causes ( p ¼ 0.06). It should be noted that the absolute number of adverse effects was small, that the meta-analysis has several limitations and that, as of this writing, it has not undergone careful scrutiny. Nevertheless, despite recent enthusiasm for the use of TZDs as hypoglycemic agents, caution is advisable in prescribing these agents until more information is available and the complex actions of peroxisome proliferatoractivated receptors (PPAR) agonists are better understood. Furthermore, it is now clear that TZDs should not be used to treat diabetic patients with heart failure or severe left ventricular dysfunction, since these agents have been shown to cause fluid retention and aggravate or precipitate heart failure even though they do not appear to adversely affect left ventricular systolic function (244). The newest classes of hypoglycemic agents used to treat diabetes are the incretin mimetics (exenetide) and the incretin enhancers (sitagliptin). Incretin is a gut-derived hormone that stimulates insulin, suppresses glucagon secretion, inhibits gastric emptying, and reduces appetite and food intake. Clinical trials with exenetide have shown reductions in fasting and post-prandial blood glucose and HbA1c with an associated weight loss. Sitagliptin has been shown to reduce HbA1c by 0.5% to 1.0% with no associated weight gain (245). The effect of these new agents on the macrovascular complications and cardiovascular outcomes of patients with type 2 diabetes is yet to be determined. Glycemic Control The question of whether “tight” glycemic control reduces the risk of cardiovascular events is still under investigation. The Diabetes Control and Complication Trial (DCCT) demonstrated that tight glycemic control reduced the occurrence or progression of diabetic microvascular complications in type 1 diabetic patients (39). However, the effect of glycemic control on macrovascular complications is less clear. In the DCCT study, a trend toward less cardiovascular morbidity and mortality in type 1 diabetics was not statistically significant. In addition, the 18-month DCCT follow-up study (EDIC) of 1325 type 1 diabetic patients demonstrated that neither intensive therapy nor the glycosylated hemoglobin level affected carotid intimal thickness (246). Nonetheless, during long-term follow-up (mean 6.5 years) intensive glycemic control reduced the risk of any cardiovascular event by 42% (p ¼ 0.02) and the risk of cardiovascular death, nonfatal MI, or stroke by 57% ( p ¼ 0.02) (247). The UKPDS established that aggressive glycemic control reduces microvascular disease in type 2 diabetics. However, the effect of this intervention on macrovascular disease was modest, the reduction of macrovascular complications failed to reach significance, and cardiovascular outcomes did not differ between patients treated with sulfonylureas or insulin (40). Nonetheless, subsequent analysis of the UKPDS data (248) found that each 1% decline in HbA1c was associated with a 21% relative reduction in diabetes-related mortality, a 14% reduction in MI, and a 37% reduction in microvascular complications (all statistically significant). The Veterans Affairs Diabetes Feasibility

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Trial (249) was a study of 350 men with a mean age of 60 years and an average duration of type 2 diabetes of 7.8 years who were randomized to either standard or intensive management. This study demonstrated no differences in total or cardiovascular mortality in the intensive versus standard treatment arms despite a 2% difference in glycated hemoglobin levels during the 27-month follow-up period. The impact of tight glycemic control at the time of cardiac surgery and PCI has also been studied extensively and remains controversial with conflicting results reported. Intraoperative hyperglycemia has been shown to be an independent risk factor for complications, including death, after cardiac surgery (250). Similarly, hyperglycemia at the time of PCI may promote restenosis in diabetic patients (251). Some studies have reported improved CABG surgery outcomes in patients treated intraoperatively with GIK (252) or with continuous insulin infusion (253), whereas others have not. For example, in a recent single-center study of intensive intraoperative insulin therapy versus conventional glycemic management during cardiac surgery, perioperative morbidity and mortality did not differ in the two groups (254). Despite these conflicting reports, the preponderance of evidence suggests that maintenance of normoglycemia and treatment with insulin-based regimens is beneficial and reduces both morbidity and mortality (albeit modestly) in critically ill patients and in patients undergoing surgical procedures or PCI (255). Although, tight glycemic control appears to have a modest effect on morbidity and mortality from cardiovascular disease in patients with diabetes mellitus, no studies have systematically evaluated the impact of intensive glucose control in diabetic patients older than 65 years. The multifactorial etiology of macrovascular disease suggests that optimal treatment of diabetic patients includes blood pressure management, correction of dyslipidemia, and modifying other prevalent risk factors (e.g., tobacco use, obesity, physical inactivity). The results of the recently reported Steno-2 study confirm that a multifactorial approach that includes intensive treatment of hyperglycemia, hypertension, dyslipidemia, microalbuminurea, and behavior modification in conjunction with aspirin reduces the risk of cardiovascular events in patients with type 2 diabetes by about 50% (256). Further large-scale, prospective, and randomized trials are necessary to determine the role of aggressive glycemic control in the prevention of diabetic macrovascular disease, particularly in older adults. REFERENCES 1. National Diabetes Statistics. The National Diabetes Clearinghouse. Available at: http://diabetes/ niddk.nih.gov/dm/pubs/statistics/index.htm#7. 2. Blonde L. State of diabetes care in the United States. Am J Manag Care 2007; 13:S36–S40. 3. Harris MI, Flegal KM, Cowie CC, et al. Prevalence of diabetes, impaired glucose tolerance in US adults: The Third National Health and Nutrition Examination Survey 1988–94. Diabetes Care 1998; 21:518–524. 4. Centers for Disease Control and Prevention. National estimates and general information on diabetes in the United States: diabetes facts sheet. Atlanta, GA. US Department of Health and Human Services, CDCP. 5. Ruderman NB, Haudenschild C. Diabetes as an atherogenic factor. Progr Cardiovasc Dis 1984; 26:373–412. 6. Stokes J, Kannel WB, Wolf PA, et al. The relative importance of selected risk factors for various manifestations of cardiovascular disease among men and women from 35 to 64 years old: 30 years of follow-up in the Framingham. Study. Circulation 1987; 75:65–73. 7. Burchfield CM, Curb JD, Rodriguez BL, et al. Glucose intolerance and 22-year stroke incidence. The Honolulu Heart Program. Stroke 1994; 25:951–957.

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8. Jorgensen H, Nakayama H, Raaschou HO, et al. Stroke in patients with diabetes. The Copenhagen Stroke Study. Stroke 1994; 25:1977–1984. 9. Tunstall PH, Kuulasmaa K, Amouyel P, et al. Myocardial infarction and coronary deaths in the World Health Organization MONICA Project. Registration procedures, event rates, and case-fatality rates in 38 populations from 21 countries in four continents. Circulation 1994; 90:583–612. 10. Chae CU, Glynn RJ, Manson JE, et al. Diabetes predicts congestive heart failure risk in the elderly. Circulation 1998; 98(suppl 1):721. 11. Huxley R, Barzi F, Woodward M. Excess risk of fatal coronary heart disease associated with diabetes in men and women. Meta-analysis of 37 prospective cohort studies. Brit Med J 2006; 332:73–78. 12. Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Pressure in Adults. Adult Treatment Panel III (ATP III). JAMA 2001; 285:2486–2497. 13. Lundberg V, Stegmayr B, Asplund K, et al. Diabetes as a risk factor for myocardial infarction: population and gender perspectives. J Intern Med 1997; 241:485–492. 14. Leibson C. Loss of the female advantage with cardiovascular disease for women with diabetes. Lupus 1999; 8:351–355. 15. Kanaya AM, Grady D, Barrett-Connor E, et al. Explaining the sex difference in coronary heart disease mortality among diabetics with type 2 diabetes mellitus. Arch Intern Med 2002; 162:1737–1745. 16. Ness J, Nassimiha D, Feria MI, et al. Diabetes mellitus in older African-Americans, Hispanics and whites in an academic hospital-based geriatrics practice. Coron Artery Dis 1999; 10:343–346. 17. Nathan DM. Long-term complications of diabetes mellitus. N Engl J Med 1993; 328: 1676–1685. 18. American Diabetes Association. Economic costs of diabetes in the U.S. in 2002. Diabetes Care 2003; 26:917–932. 19. Domurat ES. Diabetes managed care and outcomes: The Harbor City, California Kaiser Permanente diabetes care system. Am J Manag Care 1999; 5:1299–1307. 20. Atkinson MA, Maclaren NK. The pathogenesis of insulin-dependent diabetes mellitus. N Engl J Med 1994; 331:1428–1436. 21. Kaprio J, Tuomilehto J, Koskenvuo M, et al. Concordance for type 1 (insulin-dependent) and type 2 (non-insulin-dependent) diabetes mellitus in a population-based cohort of twins in Finland. Diabetologia 1992; 11:1060–1067. 22. Beck-Nielsen H, Groop LC. Metabolic and genetic characterization of prediabetic states. Sequence of events leading to non-insulin-dependent diabetes mellitus. J Clin Invest 1994; 94:1714–1721. 23. Barzilay JL, Abraham L, Heckbert S, et al. The relation of markers of inflammation to the development of glucose disorders in the elderly. Diabetes 2001; 50:2384–2389. 24. Kanaya AM, Harris T, Goodpaster BH, et al. Adipocytokines attenuate the association between visceral adiposity and diabetes in older adults. Diabetes Care 2004; 27:1375–1380. 25. Lechleimer M, Herold M, Dzien-Bischinger C, et al. Tumor necrosis factor-alpha plasma levels in elderly patients with type 2 diabetes mellitus; observations over 2 years. Diabet Med 2002; 19:949–953. 26. Santomauro A, Boden G, Silva M, et al. Overnight lowering of free fatty acids with acipimox improves insulin resistance and glucose tolerance in obese diabetic and non-diabetic subjects. Diabetes 1999; 48:1836–1841. 27. Boden G. Pathogenesis of type 2 diabetes: insulin resistance. Endocrin Clin N Am 2001; 30(4):801–815. 28. Reusch JE. Current concepts in insulin resistance, type 2 diabetes mellitus, and the metabolic syndrome. Am J Cardiol 2002; 90(suppl):G19–G26. 29. Pyorala M, Miettinen H, Halonen P, et al. Insulin resistance syndrome predicts the risk of coronary heart disease risk and stroke in healthy middle-aged men: the 22-year follow up results of the Helsinki Policemen Study. Aterioscler Thromb Vasc Biol 2002; 20:538–544.

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224. Colhoun HM, Betteridge DJ, Durrington PN, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicenter randomized placebo-controlled trial. Lancet 2004; 364:685–696. 225. Pearson TA, Denke MA, McBride PE, et al. A community-based randomized trial of Ezetimibe added to statin therapy to attain NCEP ATP III goals for LDL cholesterol in hypercholesterolemic patients: The Ezetmibe add-on to statin for effectiveness (EASE) trial. Mayo Clin Proc 2005:80:587–595. 226. Davidson MH, Armani A, McKenney JM, et al. Safety considerations with fibrate therapy. Am J Cardiol 2007; 99(suppl):C3–C18. 227. Brown BG, Zhao XQ, Chait A, et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med 2001; 345:1583–1592. 228. Guyton JR, Bays HE. Safety considerations with niacin therapy. Am J Cardiol 2007; 99 (suppl):C22–C31. 229. Nathan D. Initial management of glycemia in type 2 diabetes mellitus. N Engl J Med 2002; 347:1342–1349. 230. Monami M, Luzzi C, Lamanna C, et al. Three-year mortality in diabetic patients treated with different combinations of insulin secretagogues and metformin. Diabetes Metab Res Rev 2006; 22:477–482. 231. Johnson SP, Monster TBM, Olsen ML, et al. Risk and short-term prognosis after myocardial infarction among users of antidiabetic drugs. Am J Ther 2006; 13:134–140. 232. Plutzky J. Peroxisome proliferator-activated receptors in vascular biology and atherosclerosis. Curr Athero Rep 2000; 2:327–335. 233. Marx N. Peroxisome proliferator-activated receptor gamma and atherosclerosis. Curr Hypertens Rep 2002; 4:71–77. 234. Steinberg HO, Chaker H, Learning R, et al. Obesity/insulin resistance is associated with endothelial dysfunction: implications for the syndrome of insulin resistance. J Clin Invest 1996; 97:2601–2610. 235. Freed M, Fuell D, Menci L, et al. Effects of combination therapy with rosiglitazone and glibenclamide on PAI-antigen, PAI activity, and tPA in patients with type 2 diabetes. Diabetologica 2000; 24(suppl 1):A267. (abstr 1024). 236. Freed MI, Ratner R, Marcovina SM, et al. Effects of rosiglitazone alone and in combination with atorvastatin on the metabolic abnormalities in type 2 diabetes mellitus. Am J Cardiol 2002; 90:947–952. 237. Haffner SM, Greenberg AS, Weston WM, et al. Effect of rosiglitazone treatment on nontraditional markers of cardiovascular disease in patients with type 2 diabetes mellitus. Circulation 2002; 106:679–684. 238. Minamikawa J, Tanaka S, Yamauchi M, et al. Potent inhibitory effect of Troglitazone on carotid arterial wall thickness in type 2 diabetes. J Clin Endocrinol Metab 1998; 83: 1818–1820. 239. Hanefeld M, Marx N, Pfutzner A, et al. Anti-inflammatory effects of Pioglitazone and/or Simvastatin in high-risk patients with elevated high sensitivity C-reactive protein. J Am Coll Cardiol 2007; 49:290–297. 240. Dormandy JA, Charbonnel B, Eckland A, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive study (Prospective Pioglitazone Clinical Trial in Macrovascular Events): a randomized controlled trial. Lancet 2005; 366:1279–1289. 241. Erdman E, Dormandy JA, Charbonnel B, et al. The effect of Pioglitazone on recurrent myocardial infarction in 2445 patients with type 2 diabetes and previous myocardial infarction. J Am Coll Cardiol 2007; 49:1772–1780. 242. Kahn SE, Haffner SM, Heise MA, et al. Glycemic durability of Rosiglitazone, Metformin, or Glyburide monotherapy. N Engl J Med 2006; 355:2427–2443. 243. Nissen SE, Wolski K. Effect of Rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007; 356:2457–2471.

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244. Dargie HJ, Hildenbrandt PR, Riegger GA, et al. A randomized, placebo-controlled trial assessing the effects of Rosiglitazone on echocardiographic function and cardiac status in type 2 diabetic patients with New York Heart Association functional class I or II heart failure. J Am Coll Cardiol 2007; 49:1696–1704. 245. Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet 2006; 368:1696–1705. 246. Epidemiology of Diabetes Interventions and Complications (EDIC) Research Group. Effect of intensive diabetes treatment on carotid artery wall thickness in the epidemiology of diabetes interventions and complications. Diabetes 1999; 48:383–390. 247. The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group. Intensive diabetes treatment in patients with type 1 diabetes. N Engl J Med 2005; 353:2643–2653. 248. Stratton IM, Adler AI, Neil HA, et al. Association of glycaemia with macrovascular and microvasculoar complications in type 2 diabetes (UKPDS 35): prospective observational study. BMJ 2000; 321:405–412. 249. Abrara C, Colwell J, Nuttall F, et al. Cardiovascular events and correlates in the Veterans Affairs Diabetes Feasibility Trial. Veterans Affairs Cooperative Study on Glycemic Control and Complications in Type II Diabetes. Arch Intern Med 1997; 157:181–188. 250. Gandhi GY, Nuttall GA, Abel MD, et al. Intraoperative hyperglycemia and perioperative outcome in cardiac surgery patients. Mayo Clin Proc 2005; 80:861–866. 251. Lindsay J, Sharma AK, Canos D, et al. Preprocedural hyperglycemia is more strongly associated with restenosis in diabetic patients after percutaneous coronary intervention than is hemoglobin A1c. Cardiovasc Revasc Med 2007; 8:15–20. 252. Lazar HL, Chipkin SP, Fitzgerald CA, et al. Tight glycemic control in diabetic coronary artery bypass graft patients improves perioperative outcomes and decreases recurrent ischemic events. Circulation 2004; 109:1497–1502. 253. Furnary AP, Gao G, Gruckemeier GL, et al. Continuous insulin infusion reduces mortality in patients with diabetes undergoing coronary artery bypass grafting. J Thor Cardiovasc Surg 2003; 125:1007–1021. 254. Gandhi GY, Nuttall GA, Abel MD, et al. Intensive intraoperative insulin therapy versus conventional glucose management during cardiac surgery. Ann Intern Med 2007; 146:233–243. 255. Langley J, Adams G. Insulin-based regimens decrease mortality rates in critically ill patients: a systematic review. Diabetes Metab Res 2007; 23:184–192. 256. Gaede P, Vedel P, Larsen N, et al. Multifactorial Intervention and Cardiovascular Disease in Patients with Type 2 Diabetes. N Engl J Med 2003; 348:383–393.

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Epidemiology of Coronary Heart Disease in the Elderly Pantel S. Vokonas VA Normative Aging Study, VA Boston Healthcare System, Boston University School of Medicine, Boston, Massachusetts, U.S.A.

William B. Kannel Framingham Heart Study, Boston University School of Medicine, Boston, Massachusetts, U.S.A.

INTRODUCTION Coronary heart disease (CHD) is the central component of a broad spectrum of disease conditions affecting the heart and circulation, collectively termed atherosclerotic cardiovascular disease, that progress dramatically as age advances. Although CHD in all its clinical manifestations contributes significantly to disability and death throughout life, its toll is heaviest in the elderly (1–7). Because there is a substantial paucity of epidemiological information regarding both the development and prevention of CHD in the elderly, a thorough evaluation of the role of risk factors for CHD in older persons and the potential benefits of their amelioration would represent an important contribution to the clinical and preventive management of this disease in a large segment of the United States and world population. Considerations regarding the character of CHD and the role of risk factors for its development in older persons, which at the surface may appear straightforward, are in actuality quite complex because, of necessity, they involve interactions of the multiple and overlapping domains of aging, disease, and risk factors. This complexity is captured in the form of a Venn diagram proposed by Lakatta and his colleagues (8) (Fig. 1). In this representation, aging denotes the constellation of processes occurring over time in the adult organism resulting in characteristic alterations of structure and function of body tissues and organs including the heart and blood vessels. CHD represents “disease” in this context with underlying anatomical and pathophysiological features ultimately manifested as clinical symptoms and complications. Risk factors, in turn, index an array of atherogenic personal traits as well as lifestyle characteristics, including diet and exercise, which are associated with the development of CHD (9).

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Figure 1 Conceptualized model of interactions between aging, CHD, and risk factors for CHD in older persons. Abbreviation: CHD, coronary heart disease. Source: From Ref. 8.

Separate perspectives for each interaction among these three domains will, therefore, constitute the framework for further discussion. First, we will examine the relation of CHD occurrence to advancing age and the character of CHD in older persons. Next, we will examine how established risk factors for CHD change with advancing age and their prevalence in the elderly. Finally, we will examine associations between specific risk factors and CHD in the elderly and comment on available information regarding the efficacy of treating such factors. Each of these perspectives is systematically examined in 30-year follow-up data from the Framingham Study, focusing on findings in subjects aged 65 to 94 years. Details of the examination and laboratory procedures, response rates, and criteria for disease outcomes in the Framingham Study have previously been described (10). CHD IN THE ELDERLY A fundamental observation of cardiovascular disease epidemiology is the distinct age-related rise in the incidence of nearly all manifestations of heart and circulatory disease across the lifespan. In addition to CHD, such cardiovascular disease conditions include stroke, peripheral arterial disease, and chronic heart failure. The increase in incidence of CHD with advancing age is clearly the most striking (Fig. 2) and illustrates the most important element of the first perspective (i.e., the relation between aging and CHD). Although calculated incidence rates in men and women at far-advanced age are based on relatively small numbers of CHD events, such rates clearly follow trends established earlier in life. Also, while incidence rates in men increase linearly with age, those in women tend to increase more steeply at advanced age, approximating an exponential function. Similar trends of increasing incidence of disease events with age as noted in Figure 2 are observed in Framingham Study data for both men and women up to age 84 for nearly every major clinical manifestation of CHD, including angina pectoris, myocardial infarction, sudden death, and death due to CHD (10).

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Figure 2 Age trends in total CHD incidence for men and women. Framingham Study, 30-year follow-up. Abbreviation: CHD, coronary heart disease.

Another important observation regarding the relation of CHD and advancing age is the progressive attenuation of male predominance of disease. This is illustrated in Figure 3, which shows the marked decline in male-to-female ratio of incidence rates for CHD with the relation crossing the line of identity at far-advanced age.

Figure 3 Age-related change in male-to-female ratios for total CHD incidence. Framingham Study, 30-year follow-up. Abbreviation: CHD, coronary heart disease.

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Table 1 Specified Clinical Manifestations of CHD: Men and Women Aged 65 to 94 Years Manifestation

Men

Myocardial infarction Angina pectoris Coronary insufficiency Sudden death

Women

135/244 (55%) 73/244 (30%) 16/244 (07%) 37/244 (15%)

108/269 (40%) 123/269 (45%) 21/269 (8%) 31/269 (12%)

Source: Framingham Study, 30-year follow-up.

The character of CHD according to specified clinical manifestations for older men and women in the Framingham cohort is presented in Table 1. Data indicate the proportion of total coronary events represented by a specific manifestation. Symptomatic categories are not mutually exclusive and percentages exceed 100% because a given subject may have more than one clinical manifestation at the time of their initial presentation within a biennial period. Myocardial infarction represents the most common initial manifestation for CHD in older men, whereas angina pectoris appears to be the most common presenting feature in older women. Angina pectoris in older women frequently occurs as an isolated clinical entity. Angina pectoris in older men, however, is more often associated with acute myocardial infarction, either preceding or occurring after the acute event. Coronary insufficiency is the traditional term for unstable angina pectoris, referring to the clinical situation of either prolonged chest pain or a progressive increase in the frequency and/or intensity of ischemic chest pain. This manifestation occurs at similar frequencies in older men and women. Sudden death, as an initial manifestation of CHD, occurs somewhat more frequently in older men than in older women. Another characteristic of CHD in the elderly is the tendency for a larger proportion of myocardial infarction events to be clinically unrecognized (Table 2). The diagnosis of myocardial infarction in such instances is based on the occurrence of unequivocal electrocardiographic changes consistent with infarction between biennial examinations, where neither the subject nor his/her physician has suspected the diagnosis (11). Symptoms associated with such events are usually attributed to musculoskeletal chest discomfort, upper gastrointestinal tract upset, gall bladder disease, or other conditions. Approximately one-half of such infarctions are completely silent. Unrecognized events represent a larger proportion of all infarctions in women, and particularly older women.

Table 2 Proportion of Unrecognized Myocardial Infarctions by Age and Sex Age (yr)

Men (%)

30–44 45–54 55–64 65–74 75–84 85–95% Average

29 18 25 25 42 33 28

Source: Framingham Study, 30-year follow-up.

Women (%) –– 41 31 35 36 46 35

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CHANGES IN CHD RISK FACTORS WITH ADVANCING AGE Nearly all of the established CHD risk factors change with advancing age. These include changes in blood pressure, serum lipids, cigarette smoking, glucose metabolism, body weight, and other factors. Several age-related trends in risk factors and their prevalence in older persons are described below. This constitutes the second perspective of our discussion (i.e., the interaction between aging and risk factors). The most well-characterized change in an established CHD risk factor with age is elevation of blood pressure. In longitudinal data from the Framingham Study, systolic blood pressure is observed to rise nearly linearly with advancing age in both men and women (Fig. 4). Diastolic blood pressure, in contrast, tends to rise throughout middle age in both sexes and actually declines at advanced age. Diastolic blood pressures in women, however, usually remain 5 to 10 mmHg lower than those in men throughout the life span (1). The consistent increase in systolic blood pressure is due to progressive vascular stiffening attributable to alterations of the physicochemical properties within the media of the arterial wall, including overall thickening and changes in the nature and content of collagen, elastin, and, possibly, other structural proteins that occur with advancing age (12). This process is dissimilar to that of atherosclerosis, which underlies the preponderance of cardiovascular disease observed in older people. Although progressive elevation of systolic blood pressure with advancing age is consistently observed in nearly every western industrialized population studied, it does not appear to represent a universal feature of the aging process. Data from a number of isolated primitive populations suggests that this relation is markedly blunted (13).

Figure 4 Average age trends in systolic and diastolic blood pressure levels for men and women based on cross-sectional and longitudinal (cohort) data. Framingham Study, Biennial exams 3–10. Source: From Ref. 1.

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Possibilities accounting for differences in age-related change in blood pressure between populations likely include genetic factors as well as dietary influences, especially the higher intake of salt in industrialized nations (14). Despite its ubiquity, however, progressive elevation of systolic blood pressure with advancing age should not be construed as an innocuous concomitant of the aging process, since it clearly confers increased risk for stroke, CHD, and other cardiovascular disease events in both elderly men and women (15). Elevated diastolic blood pressure also occurs commonly in the elderly and remains an important risk factor for cardiovascular disease, particularly in older men. As a consequence of the progressive, age-related increase, primarily in systolic blood pressure, approximately 40–50% of men and women in a typical westernized population such as Framingham meet one or more of the established criteria for hypertension after the age of 65. For persons categorized as being hypertensive, isolated systolic hypertension (defined as systolic blood pressure (BP) >160 mmHg with diastolic BP
95 mmHg) accounts for nearly two-thirds of the total prevalence of hypertension in both older men and women (16). Combined hypertension, characterized by abnormal elevations of both systolic and diastolic blood pressures, accounts for less than one-third of the total prevalence. Isolated diastolic hypertension is considerably less prevalent in older men and women accounting for less than 15% of the prevalence. Blood lipids including serum total cholesterol also vary with age across the life span and trends appear to be different in women compared with men. Figure 5 shows longitudinal trends in average levels of serum cholesterol in the Framingham Study as a function of age. Note that levels in men tend to peak in early middle age and then slowly decline with advancing age. Levels in women peak later in middle age and remain relatively high until advanced age before a decline occurs. The practical implication of this trend is the relatively high prevalence of hypercholesterolemia likely to be encountered in similar populations of older women. Corresponding age trends for specific lipoprotein–cholesterol subfractions in the Framingham Study are illustrated in Figure 6. Trends for low-density lipoprotein (LDL)

Figure 5 Average age trends in serum cholesterol levels in cross-sectional and longitudinal (cohort) data. Framingham Study, Biennial exams 1–16.

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Figure 6 Average age trends in lipoprotein cholesterol subfractions. Framingham Study.

cholesterol, in general, are similar to those for serum total cholesterol. Mean levels of high-density lipoprotein (HDL) cholesterol are consistently higher in women than in men across the age span, but tend to decline slightly after menopause. Mean HDL cholesterol levels in men remain essentially unchanged throughout life. Mean values of very lowdensity lipoproteins (VLDL) tend to be higher in men than women, but levels in both men and women tend to rise throughout middle age and then remain relatively stable thereafter. Presumably, these trends reflect fluctuations in body weight occurring at corresponding ages in the sexes. The prevalence of major cardiovascular risk factors in older subjects of the Framingham Study is presented in Table 3. Data are arrayed for each decade of age from 65 to 94 years and separately for men and women. As would be expected from age trends observed earlier, hypercholesterolemia appears to be quite prevalent in older women. Glucose metabolism becomes progressively impaired with advancing age, resulting in increasing prevalence of glucose intolerance in both older men and women (17). Body weight tends to decrease at a far-advanced age. Weight loss, however, represents a reduction primarily in lean body mass (i.e., muscle and bone tissue) rather than adipose tissue. The result is an alteration of body composition in older persons with higher proportional adiposity per unit of weight (18). Despite the tendency for lower body weights at advanced age, obesity appears to be well represented in both older men and women in this cohort. The prevalence of cigarette smoking appears to decrease with advancing age. This can be attributed not only to higher mortality rates in smokers but also to discontinuation of cigarettes because of health problems or concerns in older persons. The prevalence of ECG left ventricular hypertrophy (LVH) increases with advancing age in both older men and women. From the foregoing analysis, it is clear that the majority of established risk factors for CHD in middle-aged persons are prevalent in the elderly. What remains is the task of

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Table 3 Percentage Prevalence of Cardiovascular Risk Factors in the Elderly Definite hypertension

Hypercholesterolemia

Glucose intolerance

Age (yr)

Men

Women

Men

Women

Men

Women

65–74 75–84 85–94

42.1 45.5 20.7

48.9 61.1 64.8

16.6 9.7 9.4

39.7 36.3 18.4

29.5 30.9 33.3

17.5 26.0 29.0

Obesity

Cigarette smoking

ECG-LVH

Age (yr)

Men

Women

Men

Women

Men

Women

65–74 75–84 85–94

52.2 35.4 7.7

47.8 39.3 30.0

21.9 13.9 9.4

23.0 8.5 3.2

5.5 6.0 10.4

4.2 7.8 13.0

Definite hypertension: BP>160/95 mmHg; hypercholesterolemia: serum cholesterol >250 mg/dL; glucose intolerance: blood glucose >120 mg/dL, glycosuria, or diabetes mellitus; obesity: relative weight >120%; cigarette smoking: any (Exam 15). Abbreviation: ECG-LVH, evidence of left ventricular hypertrophy on electrocardiogram. Source: Framingham Study, Exam 16.

marshaling evidence to address the question of whether or not such risk factors continue to remain operative in the development of CHD in older persons. This analysis constitutes the third and final perspective of interactions alluded to earlier (i.e., associations between specific risk factors and CHD in older persons), which will be reviewed next. ASSOCIATION BETWEEN SPECIFIC RISK FACTORS AND CHD IN THE ELDERLY Associations for a number of specific risk factors and CHD are summarized in Table 4. Putative risk factors are listed in the column on the left. Standardized, age-adjusted (bivariate) logistic regression coefficients are categorized for younger and older subjects

Table 4 Associations Between Specific Risk Factors and Incidence of Coronary Heart Disease Bivariate standardized regression coefficients (age-adjusted) Ages 35–64 Risk factors Systolic pressure Diastolic pressure Serum cholesterol Cigarettes Blood glucose Vital capacity Relative weight

Men

Women

Men

Women

0.338a 0.321a 0.322a 0.259a 0.043 –0.1 12b 0.190a

0.418a 0.363a 0.307a 0.095 0.206a –0.331a 0.264a

0.401a 0.296a 0.121 –0.017 0.1 66a –0.127 0.177c

0.286a 0.082 0.213a –0.034 0.209a –0.253a 0.124b

Significant at p < 0.001. Significant at p < 0.05. c Significant at p < 0.01. Source: Framingham Study, 30-year follow-up. a

b

Ages 65–94

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of the Framingham cohort and also arrayed separately for men and women. Regression coefficients are derived using a logistic regression model to mathematically relate the level of a risk factor or its categorical value to the development of CHD events. The magnitude of the coefficient and also the level of statistical significance reflect the strength of the association between the specific risk factor and CHD for the age group and sex under consideration. A cursory inspection of the results indicates that the majority of significant associations between risk factors and CHD, apparent in younger men and women, remain significant in older age groups but not consistently in both sexes. Systolic blood pressure, for example, demonstrates strong risk associations for CHD in younger men and women and maintains strong associations in both older men and women. The risk association for diastolic blood pressure, in contrast, appears to lose significance in older women. Serum total cholesterol demonstrates strong risk associations for CHD in younger men and women; however, the strength of this risk association clearly weakens in older men but remains significant in older women. Cigarette smoking modeled using this methodology fails to show significant risk associations in either older men or women. Blood glucose levels, as well as other parameters reflecting impaired glucose metabolism including glucose intolerance and diabetes mellitus show strong risk associations for CHD in both older men and women. Vital capacity demonstrates strong negative risk associations, particularly in older women. Of interest, significant risk associations between CHD and body weight expressed as Metropolitan Relative Weight are maintained in both older men and women. A number of these risk associations will be characterized in detail below. Similar data for associations between specific risk factors and CHD incidence can be derived using an alternative regression methodology, the Cox proportional hazards model (19). Blood Pressure and Hypertension The relation between blood pressure and CHD, particularly in older persons, represents one of the most striking risk associations in the Framingham Study. Risk relations between CHD incidence and systolic blood pressure in men and women are shown in Figure 7. CHD incidence, expressed as age-adjusted annual rate of CHD events per 1000, appears on the ordinates of left and right panels, respectively. Systolic blood pressure appears on the abscissas of both panels. Two risk relations are illustrated in each panel, one for younger men and women, aged 35 to 64, another for older men and women, aged 65 to 94. While overall incidence rates for CHD in women are substantially lower than those at corresponding blood pressures in men, the same underlying risk associations are observed. Note that CHD risk for systolic blood pressure rises with increasing pressure in all age groups and that this rise is even more striking in older than in younger persons. These trends are interpreted as marked increases in relative risk indicating that progressively higher levels of blood pressure confer additional risk for CHD. Although these trends do not establish causality, they serve to emphasize an important role for blood pressure in the extended sequence of pathophysiological events that result in manifest CHD. Also note that risk relations in older men and women are configured well above those of younger persons in each sex indicating substantially higher incidence rates for CHD at similar blood pressures. This is interpreted as an increase in absolute risk for CHD in older men and women, suggesting a substantially higher burden of disease at all levels of blood pressure in older compared with younger persons, even at normal or low blood pressures.

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Figure 7 Risk of CHD by level of systolic blood pressure according to specified age groups in men and women. Framingham Study, 30-year follow-up. Abbreviation: CHD, coronary heart disease.

Risk relations between CHD incidence and diastolic blood pressure in men and women are shown in Figure 8. Again, risk appears to rise with increasing blood pressure in all age groups (i.e., increased relative risk) and incidence rates at the same level of blood pressure are higher in older than in younger persons (i.e., increased absolute risk). Although there is a minor deviation from the nearly linear trend for the relation between

Figure 8 Risk of CHD by level of diastolic blood pressure according to specified age groups in men and women. Framingham Study, 30-year follow-up. Abbreviation: CHD, coronary heart disease.

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Table 5 Risk of CHD by Hypertensive Status According to Age and Sex Hypertensive status

Average annual age-adjusted rate per 1000 Coronary heart disease 35–64a yr

Normal (<140/90 mmHg) Mild (140–160/90–95 mmHg) Definite (>160/95 mmHg)

65–94a yr

Men

Women

Men

Women

8 15 21

3 7 10

14 28 41

11 16 22

All trends significant at p < 0.001. Source: Framingham Study, 30-year follow-up. a

diastolic blood pressure and CHD incidence in older men, the relation maintains strong statistical significance. In contrast, the deviation in the relation corresponding to the fourth level of diastolic blood pressure (95–104 mmHg) in older women yields a statistically insignificant result using the logistic regression model, despite an apparent upward curvilinear trend. Although the discontinuities in these curves remain unexplained, these findings suggest a more consistent and reliable role for systolic compared with diastolic blood pressure as a predictor for CHD in both elderly men and women. Risk gradients for CHD that, in general, are similar in direction and magnitude to those suggested earlier are observed when individuals are classified according to hypertensive status instead of absolute levels of blood pressure (Table 5). For all age and sex groups considered, the overall risk of CHD is two to three times higher in subjects with definite hypertension compared with normotensives, while risk is intermediate for those with mild hypertension. Absolute risk is two to three times higher in older subjects, both in men and women, and risk is nearly always higher in men than in women, regardless of age. Similar patterns of risk attributable to hypertension have been observed specifically for cerebrovascular events, heart failure, and peripheral vascular disease (15). When considered alone, isolated systolic hypertension also confers substantial risk for CHD and other cardiovascular disease outcomes. Randomized clinical trials established the efficacy of treating combined elevations of systolic and diastolic blood pressures in older hypertensives (20,21), but uncertainty remained regarding the treatment of isolated systolic hypertension. The findings of the Systolic Hypertension in the Elderly Program (SHEP) served to dispel much of this uncertainty (22). This study documented impressive reductions in total numbers of fatal and nonfatal strokes in the active treatment group compared with the placebo group. Statistically significant reductions in nonfatal myocardial infarctions and coronary death, as well as combined CHD and total cardiovascular disease outcomes, were also noted in the group on active treatment. There appeared to be little or no evidence in this study that lowering of either systolic or diastolic blood pressure resulted in an increased risk of CHD events or mortality, particularly at the lower end of the distribution for blood pressure, the so-called J-shaped curve. Six other clinical trials of drug therapy for hypertension in the elderly that included patients with isolated systolic hypertension also showed beneficial effects (23–28). In addition to substantial reductions in cerebrovascular events and heart failure, the majority of intervention studies of drug therapy for hypertension in older persons have consistently

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demonstrated either beneficial trends or significant reductions in CHD events and mortality. In contrast, drug therapy is less consistently associated with improved CHD outcomes in clinical trials involving predominantly middle-aged hypertensives (20,21,29). The clinical evaluation and treatment of the elderly hypertensive patient are discussed in chapter 20. Blood Lipids The risk of CHD in older persons attributable to serum lipids represents an area of considerable uncertainty and controversy. Relations between CHD incidence and serum total cholesterol in the Framingham Study are shown in Figure 9. Separate trends are plotted in younger and older subjects for men and women, respectively. Note that absolute risk is substantially increased in older compared with younger men. Note also that relative risk clearly rises over the entire distribution of serum total cholesterol in younger as well as older men. The break in continuity of the risk relation at the fourth level of the distribution in older men, however, yields results that narrowly miss statistical significance both in bivariate (age-adjusted) and multivariate estimates using the logistic regression model, whereas the association remains strongly predictive in younger men. Although incidence rates for CHD at corresponding levels of cholesterol are lower in women than those in men, the same overall pattern pertains (i.e., an increase in both absolute and relative risk). In this instance, however, statistical significance is maintained in both younger and older women. The finding that serum total cholesterol loses strength as a risk factor for CHD, particularly in older men of the Framingham cohort, has resulted in serious misinterpretation by some authors who have used this information to argue that serum lipids are not important risk factors for CHD in the elderly and that neither detection nor treatment is justified (30,31). However, this view is not warranted, since several other studies have clearly validated the role of serum total cholesterol as a predictor of CHD events in older men (32–38) and also older women (32,34,38).

Figure 9 Risk of CHD by level of serum cholesterol according to specified age groups in men and women. Framingham Study, 30-year follow-up. Abbreviation: CHD, coronary heart disease.

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Despite these findings, however, a meta-analysis encompassing data from 22 U.S. and international cohort studies concluded that serum cholesterol did indeed lose strength as a risk predictor for CHD mortality in older men and also in older women (39), a finding consistent with original observations made in data from the Framingham Study. Cholesterol emerges as a significant predictor of CHD death when steps are taken to adjust for factors related to frailty or other comorbid conditions that serve to confound this risk association (40,41). Focusing on serum cholesterol as the sole measure of risk for CHD attributable to serum, lipids should now be considered obsolete based on our current understanding of lipoprotein subfractions and the availability of standardized laboratory methods to measure them in clinical practice. Substitution of either LDL or HDL cholesterol in the regression model fully restores statistical predictability for the risk relation between serum lipids and CHD (42). HDL cholesterol, in particular, has emerged as an important lipid moiety that adds substantial precision to assessing coronary risk at limited additional cost (43). Construction of a serum cholesterol/HDL ratio provides a highly accurate characterization of CHD risk in older men and women in the Framingham Study, which is illustrated in Figure 10. Indeed, data from Framingham as well as other studies confirm the overall reliability of the cholesterol/HDL ratio in assessing CHD risk in younger and older persons and in men as well as women (34,42,44,45). The rationale for this approach is that the ratio reliably captures the effect of a dynamic equilibrium of lipid transport into and out of body tissues, possibly including the intima of blood vessels. Several studies have suggested that serum triglycerides may be important predictors for CHD in either older men or older women, but not consistently in both sexes (34,42,44,46). Despite these observations, the present consensus holds that elevated levels of serum triglycerides represent a risk marker for obesity, glucose intolerance, and low HDL levels, all of which confers risk for CHD and, to the extent possible, deserve preventive attention. Data from intervention studies using dietary measures or drug therapy demonstrate the benefit of lipid alteration in reducing risk of CHD events, particularly in middle-aged

Figure 10 Risk of CHD by total/HDL cholesterol ratios among men and women aged 50 to 90 years. Framingham Study, 26-year follow-up. Abbreviations: CHD, coronary heart disease; HDL, high-density lipoprotein.

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men (47,48). However, despite the high prevalence of lipid abnormalities in older adults, limited data are available from clinical trials regarding the safety and efficacy of treating these abnormalities, especially in the very elderly. Therefore, widespread application of drug therapy to reduce risk of CHD in older persons as an element of primary prevention is not warranted at the present time. Of considerable interest, information from five large clinical trials makes a compelling case for reducing elevated or even average levels of LDL cholesterol with drugs in patients with established CHD: angina pectoris or following myocardial infarction (48–54). Drug therapy for the secondary prevention of CHD events (i.e., in persons with preexisting CHD) appears to be beneficial in both middle-aged and older patients of both sexes. Most recent clinical trials have also demonstrated that statin therapy reduces the incidence of stroke events (55). Current management of hypercholesterolemia for an older person considered to be at risk should consist of a highly individualized approach beginning with appropriate dietary measures and weight control before initiating a trial of specific drug therapy, preferably at lower doses, to achieve a carefully monitored lipid-lowering effect (56). Cigarette Smoking Cigarette smoking fails to demonstrate strong risk associations for total CHD events in either older men or older women using the logistic regression methodology indicated in Table 4. Significant risk associations, however, are discerned between cigarette smoking and death due to CHD (10). One explanation for this phenomenon is that smoking may be more closely related to lethal events than to outcomes composed of combinations of morbid and lethal events (55). Another explanation is that the cross-sectional pooling approach used in the analysis may classify long-term smokers who have discontinued cigarettes for relatively brief periods as nonsmokers, in effect diluting the strength of the association between the risk factor and the outcome (56). Because of these difficulties, the most reliable approach to assessing risk associations between cigarette smoking and cardiovascular morbidity or mortality is to model these events prospectively for defined categories of smoking behaviors (e.g., current smoker, former smoker, and never smoker) and for longer time intervals. Such approaches yield strong risk associations between cigarette smoking and a broad array of cardiovascular outcomes, including CHD, stroke, and peripheral arterial disease, even in older men and women. These observations have been documented using data from Framingham as well as other studies (33,57–61). Reducing the risk of cardiovascular disease is not the only reason to encourage discontinuation of cigarettes in older persons. Cigarettes contribute to the development of chronic bronchitis and obstructive lung disease as well as lung cancer and other malignancies. These conditions also exact a heavy toll in terms of disability and death in the elderly. Thus, the clinician can make a compelling argument that it is never too late to stop smoking and extend appropriate advice and encouragement to assist patients in their effort to discontinue cigarettes. Glucose Tolerance and Diabetes Mellitus Impaired glucose metabolism is not only highly prevalent in the elderly, but also confers substantial risk for CHD as well as other cardiovascular events in both older men and women. Various measures of glucose tolerance are employed and nearly all demonstrate significant risk associations with CHD in the Framingham Study (10). These measures include blood glucose levels, glycosuria, and the composite risk categories designated as glucose intolerance and diabetes mellitus. Although diabetes mellitus confers enhanced

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Figure 11 Age-adjusted incidence rates for CHD based on diabetic status classified according to age and sex. Solid bar ¼ diabetic; open bar ¼ nondiabetic; RR ¼ risk ratio diabetic/nondiabetic. Source: From Ref. 62.

risk for both younger and older men, the impact of diabetes mellitus on CHD risk is even greater for both younger and older women (62) (Fig. 11). Similar patterns of risk are noted for coronary and cardiovascular mortality (10,62,63). Diabetes also emerges as an important risk factor in the development of chronic heart failure, particularly in older women with insulin-dependent diabetes mellitus (64). Presumably, the microvascular disease that is unique to diabetes, as well as other mechanisms, serves to produce progressive damage to heart muscle, ultimately resulting in compromised ventricular function and heart failure. There is little evidence that control of hyperglycemia, either by oral hypoglycemic agents or insulin, effectively forestalls either the development or complications of cardiovascular disease (62,65), although encouraging trends in this regard were identified in the Diabetes Control and Complications Trial (66). Available evidence would, therefore, suggest that there is more to be gained in reducing risk by correcting associated cardiovascular risk factors in persons with diabetes than by attention confined to early detection and control of hyperglycemia (67). Left Ventricular Hypertrophy LVH as determined by the electrocardiogram (ECG-LVH emerges as a strong risk factor for CHD in older men and women (Fig. 12). Marked increases in CHD incidence are noted in persons with voltage criteria for LVH alone, and additional risk is conferred by

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Figure 12 Risk of CHD according to ECG-LVH status. Framingham Study, 30-year follow-up. Abbreviations: CHD, coronary heart disease; ECG-LVH, evidence of left ventricular hypertrophy on electrocardiogram.

definite LVH, which includes repolarization (ST and T wave) abnormalities consistent with LVH in addition to voltage criteria. These electrocardiographic findings presumably reflect abnormalities of myocardial structure and function related to early compromise of the underlying coronary circulation that antedate the development of clinical manifestations of CHD (68–70). In this context, LVH (LV mass), as determined by echocardiography, has emerged as an extremely potent independent predictor of CHD as well as other cardiovascular disease events, especially in older persons (71,72). Body Weight Of considerable interest is the finding that increased body weight represents a significant risk marker for CHD even at advanced age. The association between body weight and risk for CHD in older subjects of the Framingham Study is illustrated in Figure 13. Note that while CHD risk rises more strikingly with increasing body weight in older men, trends in older women clearly indicate enhanced risk at higher body weights. These data are consistent with reports from other studies (73,74). Progressive increases in body weight occurring earlier in life correlate closely with changes in the levels of several risk factors considered to be more directly related to the pathogenesis of atherosclerosis (75). These include increases in blood pressure, serum cholesterol and triglycerides, blood glucose, and a reduction in HDL cholesterol. These findings emphasize the need to incorporate measures ultimately designed to either control or, if necessary, gradually reduce body weight as part of risk management even in older persons. Although a beneficial effect of weight reduction on CHD events in older adults has not been established, weight control should be incorporated into the initial management of elderly patients with hypertension, dyslipidemia, and diabetes, or combinations of these conditions.

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Figure 13 Risk of CHD according to body weight in men and women aged 65 to 94 years. Framingham Study, 30-year follow-up. Abbreviation: CHD, coronary heart disease.

Vital Capacity Vital capacity is a simple and sensitive clinical technique for assessing compromise of pulmonary or cardiac function, or both, in individuals of all ages. In contrast to inconsistent risk associations with CHD found in younger subjects, vital capacity emerges as an important risk factor in the elderly, particularly with respect to risk for major coronary events (2,10). Vital capacity normally declines with advancing age, an effect that is strongly exacerbated by cigarette smoking and obesity (76). Diminished vital capacity in older people is also correlated with loss of muscular strength as assessed by handgrip, presumably reflecting overall neuromuscular debility (77). Low vital capacity is also a strong predictor of cardiovascular mortality, as well as mortality from all causes. Measurement of this parameter, therefore, should be considered as part of the standard risk assessment of all older patients. Heart Rate Recent data from the Framingham Study demonstrate that higher resting heart rate confers additional risk for CHD in both younger and older men, although no association is observed in younger or older women (2,10). An explanation for this finding is not readily apparent. Heart rate may be a more sensitive indicator of underlying cardiac dysfunction in men than in women, or the net impact of sympathetic nervous system influences in precipitating CHD events may be greater in men. High heart rates may also reflect physical deconditioning. Physical Activity Accumulating evidence suggests that lifetime vigorous physical activity may forestall CHD in the elderly (78–80). Previously reported data from Framingham indicated that

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overall mortality including coronary mortality was inversely related to level of physical activity in middle-aged men (81), and a benefit in older men was also suggested. Although regular physical activity in the elderly is desirable and should be strongly encouraged, it would be unwise to place undue emphasis on this approach alone for reducing the risk for CHD. Prevalent CHD An important predictor of CHD events at all ages is the presence of antecedent CHD. It is, therefore, of interest that several of the risk factors associated with the initial development of CHD in the elderly not only continue to have strong correlations with prevalent disease but also maintain predictive associations for new CHD events in older persons with preexisting disease (34,36,82–84). Serum lipids, cigarette smoking, and diabetes appear to be more prominent in this context than hypertension. Blood pressure may fall substantially following myocardial infarction, especially extensive anterior myocardial infarction that carries a poorer prognosis, thereby confounding the relation between hypertension and CHD morbidity and mortality (85). Blood pressure, however, reemerges as a significant predictor of recurrent CHD events in long-term survivors of myocardial infarction (86). These findings serve to emphasize the critical role of controlling risk factors in older persons with established CHD. Effective treatment of hypertension, discontinuation of cigarettes, and adequate control of hyperglycemia are important preventive measures in the clinical management of such individuals. Similarly, the potential benefit of lipidlowering drugs in older persons with established CHD has been previously noted. Other Risk Factors Several hematological or hemostatic factors have been described as risk variables in the Framingham Study. Hematocrit appears to contribute to CHD in younger men and women but not in older persons (10). White blood cell count, which was strongly correlated with the number of cigarettes smoked per day, hematocrit, and vital capacity, was associated with enhanced risk for CHD and other cardiovascular endpoints in older men, both in smokers and nonsmokers, but only in women who smoked (87). These data are consistent with reports from other studies (88). Advanced age is associated with significant increases in plasma fibrinogen and von Willebrand factor levels as well as measures reflecting impaired fibrinolytic function: plasminogen-activator inhibitor (PAI) and tissue plasminogen-activator antigens (PAAs), contributing to a prothrombotic state in the elderly (89). In the Framingham Study, plasma fibrinogen showed strong risk associations for CHD and other cardiovascular disease outcomes in men, including older men (90), similar to findings from other studies (91). Significant risk associations, however, were not apparent in older women. Considerably less information is currently available regarding the cardiac risk potentially attributable to PAI and PAAs in older persons. Elevated blood levels of homocysteine appear to be an independent risk factor for cardiovascular disease, particularly stroke in older persons, a finding confirmed in Framingham and other studies (92). Homocysteine has multiple deleterious effects on vascular endothelium ultimately leading to thrombosis (93). Factors that may increase homocysteine levels include advancing age, renal insufficiency, vitamin-deficient diets, and drugs that interact with folic acid and vitamins B6 and B12. Combinations of folic acid and vitamins B6 and B12 are usually employed for therapy. Data from several recent large controlled clinical trials, however, have failed to demonstrate a significant benefit of

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lowering homocysteine on subsequent atherothrombotic events (94–96). This has served to limit the enthusiasm of many clinicians to screen for and treat hyperhomocysteinemia in patients with established CHD. Because of the relative safety and inexpensive nature of such therapy, some clinicians prefer to maintain high-risk patients on these vitamin preparations. The possibility that reducing homocysteine levels may have a role in the primary prevention of CHD has yet to be confirmed. Inflammatory phenomena are now recognized as playing a central role in the extended pathophysiological processes resulting in atherosclerosis and its thrombotic complications. Levels of high-sensitivity C-reactive protein (CRP), a marker of systemic inflammation, represent a strong predictor of both initial and recurrent CHD events (97,98). Because drugs such as aspirin and statins can attenuate this inflammatory process, CRP may have an important role in identification of apparently healthy older individuals, particularly women, at enhanced risk for CHD who may benefit from primary prevention (99). CRP levels can also serve as a clinically useful guide for an array of cardioprotective therapies already validated in the secondary prevention of CHD events in patients with established CHD, irrespective of age. A key study in this context evaluated the utility of combining CRP with other inflammatory markers including soluble tumor necrosis factor (TNFa) receptor types 1 and 2 (sTNF-R1 and sTNF-R2) and interleukin 6 (IL6) in middle-aged and older men and women (100). High levels of IL6 and CRP were significantly related to risk of CHD in both sexes, whereas high levels of soluble TNFa were significant only in women. Although all associations were attenuated following statistical adjustment for lipid and nonlipid factors, CRP alone retained power as an independent predictor for CHD. Myeloperoxidase (MPO) is a hemiperoxidase secreted by both white blood cells and activated phagocytes at sites of inflammation including atherosclerotic lesions. Accumulating evidence suggests that MPO may play a causal role in plaque vulnerability leading to subsequent rupture (98). A recent prospective study demonstrated that serum MPO levels are associated with future risk of CHD events in apparently healthy middleaged and older persons (101). Assays of natriuretic peptides have already established their utility in the evaluation and management of patients with heart failure. Both brain plasma natriuretic peptide and N-terminal atrial natriuretic peptide levels are elevated in the elderly, especially in older women (102), but neither peptide level was associated with the subsequent risk of CHD events (103). Both peptide levels, however, were associated with significant risk for stroke, atrial fibrillation, heart failure and related death. Excess risk was apparent at natriuretic peptide levels well below those consistent with heart failure. Similar findings were reported in the recently completed Prevention of Events with AngiotensinConverting Enzyme Inhibition (PEACE) Trial (104). In a recent investigation from the Framingham Heart Study, an array of biomarkers was used to predict the risk of major cardiovascular events and death (105). These included CRP, both natriuretic peptides, aldosterone, renin, fibrinogen, D-dimer, PAI type 1, homocysteine, and urinary albumin-to-creatinine ratio. The biomarkers that most strongly predicted major cardiovascular events were B-type natriuretic peptide and urinary albumin-to-creatinine ratio. The authors concluded that the use of 10 contemporary biomarkers adds only moderately to traditional cardiac risk factors in assessing risk for CHD. The potential utility of circulating vascular cell adhesion molecules (VCAMs) as risk markers for CHD at advanced age has received limited attention. Both VCAM-1 and intercellular adhesion molecule-1 (ICAM-1) appear to be elevated in older men and women irrespective of coronary risk status or established CHD (106). E-selectin was not

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correlated with age. Such molecules appear to have limited value as risk predictors for CHD in the elderly at the present time. An extensive array of psychosocial, occupational, dietary, and other factors have been described as putative risk parameters for CHD in the Framingham Study (9,107); however, only limited information is available regarding specific associations of these factors with CHD in older persons. Family history of CHD is strongly related to early development of CHD (before age 60) in both men and women in the Framingham Study, and predictive associations also remain significant for the late onset of CHD (108). CHD RISK PROFILES IN THE ELDERLY Although associations between a specific risk factor and CHD can be considered in isolation as a single relation, in many instances combinations of several risk factors may contribute to the observed risk profile, especially in older persons. Risk of CHD, in such instances, can be reliably estimated by synthesizing several risk factors into a composite score, based on a multiple logistic function (109–111). Risk factors are assessed by standard clinical procedures (smoking history, blood pressure, and electrocardiogram) and by routine laboratory studies (serum total cholesterol, HDL cholesterol, and blood glucose). This type of composite index permits detection of individuals at relatively high risk, either on the basis of marked elevation of a single factor or because of marginal abnormalities of several risk factors. This multivariate risk scenario is illustrated in Figure 14, which characterizes the risk of CHD at two predefined levels of serum cholesterol and then considers changes in the levels or values of other risk factors toward worsening risk, as indicated in the accompanying table. Note that risk increases progressively with the addition of other risk factors for both categories of serum cholesterol, even in instances where a factor such as cigarette smoking has a relatively weak risk association with CHD when considered alone. The major risk factors including age when taken together, explain only a limited proportion of the variance of CHD incidence in younger as well as older persons (109–111). It is likely that other major risk attributes exist among both the young and the elderly, but are yet to be identified. It must be emphasized, however, that the factors that

Figure 14 Risk of CHD of two levels of serum cholesterol according to specified levels or categories of other risk factors for 70-year-old women in the Framingham Study. Abbreviation: CHD, coronary heart disease.

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have already been delineated do identify high-risk subgroups of the elderly population that should be targeted for preventive management (112,113). PERSPECTIVES FOR PRIMARY PREVENTION OF CHD IN THE ELDERLY An important principle of prevention is the concept that measures limiting the effect of known risk factors should be initiated as early in life as possible to minimize the subsequent development of disease in both the young and the elderly. It is inappropriate to conclude, however, that modifications of risk factors initiated at advanced age are unlikely to be effective in reducing the toll of related disease in older persons. A simple but important observation in this context is that the incidence of CHD in the elderly varies widely within distributions of continuous risk factors such as blood pressure or serum cholesterol. Incidence also appears to differ markedly for values of categorical variables such as the presence or absence of LVH. In addition, data presented earlier indicate that the incidence of CHD, as well as other cardiovascular disease events, is not only substantially higher in populations of older persons but also continues to rise with advancing age across the life span. Because incidence is usually higher in older persons, the beneficial effect of a given intervention such as treatment of hypertension or hypercholesterolemia, as assessed by reduction in relative risk, may be similar to or lower than that observed in younger persons (2,20,114). In many such instances, however, the impact measured as a difference in absolute risk, reflecting reduction in the number of adverse disease outcomes, is actually greater in the elderly. A corollary of this is that a smaller number of older compared with younger people need to be treated to prevent an equivalent number of disease events. These considerations are more relevant today than ever before. Recently, a marked and progressive decline in mortality due to coronary and cardiovascular disease has occurred in the United States and several other industrialized nations (115). Age-specific trends indicate decreasing mortality due to CHD and cardiovascular disease, both in the elderly and in younger adults of both sexes. Similar trends in cardiovascular mortality have been identified in the Framingham population (116). At the same time, the prevalence of several coronary risk factors such as untreated hypertension, elevated serum cholesterol levels, and cigarette smoking has diminished in the population at large including the elderly, while major advances have occurred in the diagnosis and treatment of CHD. Importantly, in a recent analysis approximately 50% of the decline in cardiovascular mortality was attributed to the success of widespread implementation of primary preventive strategies resulting in lower levels of major risk factors, while the remaining 50% was attributed to advances in diagnosis and treatment of established disease (115). In this context, hypertension clearly emerges as the dominant, potentially remediable risk factor for both CHD and cerebrovascular disease morbidity and mortality in the elderly. Hypertension is highly prevalent in the aged, easily detected, and can be corrected by the careful application of appropriate measures including drug therapy. As mentioned earlier, direct evidence from clinical trials has already established the efficacy of antihypertensive measures in reducing the frequency of both stroke and CHD events in elderly hypertensives. Available information also makes a compelling case for discontinuation of cigarettes at all ages including the elderly. Information is needed, however, regarding the feasibility and effectiveness of nonpharmacological approaches such as diet and weight reduction in treating older persons with hypertension and lipid

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abnormalities, both as initial therapy and as adjuncts to specific drug therapy. Also, it is critically important that the efficacy and safety of drug therapy for the treatment of lipid abnormalities in the elderly for the purpose of primary prevention be established in large, well-designed clinical trials. Lack of such information severely limits our confidence in extending what may be a potentially highly beneficial preventive measure to greater numbers of older persons. ACKNOWLEDGMENTS The authors wish to thank Claire Chisholm for her invaluable assistance in preparing this manuscript. This work was supported by the Cooperative Studies Program/ERIC of the Department of Veterans Affairs and the Massachusetts Veterans Epidemiology and Research Information Center (MAVERIC), the Visiting Scientist Program of the Framingham Heart Study, and grant nos. NO1-HV-92922, NO1-HV52971, and 5T32HL-07374-13 of the National Institutes of Health. REFERENCES 1. Kannel WB, Gordon T. Evaluation of cardiovascular risk in the elderly: the Framingham Study. Bull N Y Acad Med 1978; 54:573–591. 2. Kannel WB, Vokonas PS. Primary risk factors for coronary heart disease in the elderly: the Framingham study. In: Wenger NK, Furberg CD, Pitt E, eds. Coronary Heart Disease in the Elderly. New York: Elsevier Science Publishing, 1986:60–92. 3. Kannel WB, Vokonas PS. Demographics of prevalence, incidence and management of coronary heart disease in the elderly and in women. Ann Epidemiol 1992; 2:5–14. 4. Rich MW. Epidemiology, clinical features, and prognosis of acute myocardial infarction in the elderly. Am J Geriatr Cardiol 2006; 15(1):7–11. 5. Forman DE, Bernal JLG, Wei JY. Management of acute myocardial infarction in the very elderly. Am J Med 1992; 93:315–326. 6. Wenger NK. Cardiovascular disease in the elderly. Curr Probl Cardiol 1992; 10:615–690. 7. Kannel WB, Doyle JT, Shepard RJ, et al. Prevention of cardiovascular disease in the elderly. 18th Bethesda Conference: Cardiovascular Disease in the Elderly. J Am Coll Cardiol 1987; 19 (suppl A):25A–28A. 8. Lakatta EG. Cardiovascular function in later life. Cardiovasc Med 1985; 10:37–40. 9. Kannel WB, Sytkowski PA. Atherosclerosis risk factors. Pharmacol Ther 1987; 32:207–235. 10. Cupples LA, D’Agostino RB. Section 34. Some risk factors related to the annual incidence of cardiovascular disease and death using pooled repeated biennial measurements: Framingham Heart Study, 30-year follow-up. In: Kannel WB, Wolf PA, Garrison RJ, eds. The Framingham Study: An Epidemiological Investigation of Cardiovascular Disease. Bethesda, MD: National Heart, Lung, and Blood Institute, publication No. (NIH) 87-2703, 1987. 11. Kannel WB, Abbott RD. Incidence and prognosis of unrecognized myocardial infarction: an update from the Framingham Study. N Engl J Med 1984; 11:1144–1147. 12. Mitchell GF, Parise H, Benjamin EJ, et al. Changes in arterial stiffness and wave reflection with advancing age in healthy men and women: the Framingham Heart Study. Hypertension 2004; 43(6):1239–1245. 13. Maddocks I. Possible absence of essential hypertension in two complete Pacific Island populations. Lancet 1976; 2:327–331. 14. Avolio AP, Deng FQ, Li WG, et al. Effects of aging on arterial distensibility in populations with high and low prevalence of hypertension: comparison between urban and rural communities in China. Circulation 1985; 71:202–210.

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59. Kannel WB, Higgins M. Smoking and hypertension as predictors of cardiovascular risk in population studies. J Hypertens 1990; 8(suppl 5):S3–S8. 60. Benfante R, Reed D, Frank J. Does smoking have an independent effect on coronary heart disease incidence in the elderly? Am J Public Health 1991; 81:897–899. 61. LaCroix AZ, Lang J, Scherr P, et al. Smoking and mortality among older men and women in three communities. N Engl J Med 1991; 324:1619–1625. 62. Vokonas PS, Kannel WB. Diabetes mellitus and coronary heart disease in the elderly. In: Aronow W, Tresch D, eds. Clinics in Geriatric Medicine, Vol 12, no. 1. Philadelphia, PA: WB Saunders, 1996:69–78. 63. Fox CS, Coady S, Sorlie PD, et al. Increasing cardiovascular disease burden due to diabetes mellitus: the Framingham Heart Study. Circulation 2007; 115(2):1544–1550. 64. Kannel WB, Hjortland M, Castelli WB. Role of diabetes in congestive heart failure: the Framingham Study. Ann Intern Med 1970; 72:813–822. 65. Wilson PWF, Cupples L, Kannel WB. Is hyperglycemia associated with cardiovascular disease? The Framingham Study. Am Heart J 1991; 121:586–590. 66. Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes in the development and progression of long-term complications in insulindependent diabetes mellitus. N Engl J Med 1993; 329:986–997. 67. Gaede P, Vedel P, Larsen N, et al. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 2003; 348:383–393. 68. Kannel WB, Dannenberg AL, Levy D. Population implications of electrocardiographic left ventricular hypertrophy. Am J Cardiol 1987; 60:851–931. 69. Aronow WS. Left ventricular hypertrophy. J Am Geriatr Soc 1992; 40:71–80. 70. Levy D, Salomon M, D’Agostino RB, et al. Prognostic implications of baseline electrocardiographic features and their serial changes in subjects with left-ventricular hypertrophy. Circulation 1994; 90:1786–1793. 71. Aronow WS, Koenigsberg M, Schwartz KS. Usefulness of echocardiographic left ventricular hypertrophy in predicting new coronary events and atherothrombotic brain infarction in patients over 62 years of age. Am J Cardiol 1988; 61:1130–1132. 72. Levy D, Garrison RJ, Savage DD, et al. Left ventricular mass and incidence of coronary disease in an elderly cohort. The Framingham Heart study. Ann Intern Med 1989; 110: 101–107. 73. Manson JE, Colditz GA, Stampfer MJ, et al. A prospective study of obesity and risk of coronary heart disease in women. N Engl J Med 1990; 322:882–889. 74. Adams KF, Schatzkin A, Harris TB, et al. Overweight, obesity, and mortality in a large prospective cohort of persons 50 to 71 years old. N Engl J Med 2006; 35(8):763–778. 75. Borkan GA, Sparrow D, Wisnieski C, et al. Body weight and coronary risk: patterns of risk factor change associated with long-term weight change. The Normative Aging Study. Am J Epidemiol 1986; 124(3):410–419. 76. Sparrow D, Weiss ST. Pulmonary system. In: Rowe JW, Besdine R, eds. Geriatric Medicine. Boston: Little Brown, 1988:266–275. 77. Kannel WB, Hubert H, Lew EA. Vital capacity as a predictor of cardiovascular disease: the Framingham Study. Am Heart J 1983; 34:1022–1033. 78. Donahue RP, Abbott RD, Reed DM, et al. Physical activity and coronary heart disease in middle-aged and elderly men: the Honolulu Heart Program. Am J Public Health 1988; 78: 683–685. 79. Berlin JA, Colditz GA. A meta-analysis of physical activity in the prevention of coronary heart disease. Am J Epidemiol 1990; 132:612–628. 80. Paffenbarger RS Jr., Hyde RT, Wing AL, et al. The association of changes in physical activity level and other lifestyle characteristics with mortality among men. N Engl J Med 1993; 328:538–545. 81. Kannel WB, Belanger AJ, D’Agostino RB, et al. Physical activity and physical demand on the job and risk of cardiovascular disease and death: the Framingham Study. Am Heart J 1986; 112:820–825.

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82. Wong ND, Wilson PWF, Kannel WB. Serum cholesterol as a prognostic factor after myocardial infarction: the Framingham Study. Ann Intern Med 1991; 115:687–697. 83. Simons LA, Friedlander Y, McCalluni J, et al. The Dubbo Study of health of elderly: correlates of coronary heart disease at study entry. J Am Geriatr Soc 1991; 39:584–590. 84. Applegate WB, Hughes JP, Vander-Zwaag R. Case-control study of coronary heart disease risk factors in the elderly. J Clin Epidemiol 1991; 44:409–415. 85. Kannel WB, Sorlie PD, Castelli WP, et al. Blood pressure and survival after myocardial infarction. The Framingham Study. Am J Cardiol 1980; 45:326–330. 86. Wong ND, Cupples LA, Ostfeld AM, et al. Risk factors for long-term coronary prognosis after initial myocardial infarction. The Framingham Study. Am J Epidemiol 1989; 130:469–480. 87. Kannel WB, Anderson K, Wilson PWF. While blood cell count and cardiovascular disease. JAMA 1992; 267:1253–1256. 88. de L, Labry O, Campion EW, Glynn RJ, et al. White blood cell count as a long-term predictor of mortality: results over 18 years from the Normative Aging Study. J Clin Epidemiol 1990; 43:153–157. 89. Tofler GH, Massaro J, Levy D, et al. Relation of the prothrombotic state to increasing age (from the Framingham Offspring Study). Am J Cardiol 2005; 96(9):1280–1283. 90. Kannel WB, Wolf PA, Castelli WP, et al. Fibrinogen and risk of cardiovascular disease. The Framingham Study. JAMA 1987; 258:1183–1186. 91. Lowe GD, Rumley A. Fibrinogen and its degradation products as thrombotic risk factors. Ann N Y Acad Sci 2001; 936:560–565. 92. Bostom AG, Rosenberg IH, Silbershatz H, et al. Nonfasting plasma total homocysteine levels and stroke incidence in elderly persons: the Framingham Study. Ann Intern Med 1999; 131(5): 352–355. 93. Haynes WG. Hyperhomocysteinemia, vascular function and atherosclerosis: effects of vitamins. Cardiovasc Drugs Ther 2002; 16(5):391–399. 94. Lonn E, Yusuf S, Arnold MJ, et al. Heart outcomes prevention evaluation (HOPE) 2 investigators. Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med 2006; 354(15):1567–1577. 95. Bonaa KH, Njolstad I, Ueland PM, et al. Homocysteine lowering and cardiovascular events after acute myocardial infarction. N Eng J Med 2006; 354(15):1578–1588. 96. Zoungas S, McGrath BP, Branley P, et al. Cardiovascular morbidity and mortality in the Atherosclerosis and Folic Acid Supplementation Trial (ASFAST) in chronic renal failure: a multicenter, randomized, controlled trial. J Am Coll Cardiol 2006; 47(6):1108–1116. 97. Ridker PM. Clinical application of C-reactive protein for cardiovascular disease detection and prevention. Circulation 2003; 107(3):363–369. 98. Tsimikas S, Willerson JT, Ridker PM. C-reactive protein and other emerging blood biomarkers to optimize risk stratification of vulnerable patients. J Am Coll Cardiol 2006; 47(8): C19–C31. 99. Cook NR, Buring JE, Ridker PM. The effects of including C-reactive protein in cardiovascular risk prediction models for women. Ann Intern Med 2006; 145:21–29. 100. Pai JK, Pischon T, Ma J, et al. Inflammatory markers and the risk of coronary heart disease in men and women. N Engl J Med 2004; 351(25):2599–2610. 101. Meuwese MC, Stroes ESG, Hanen SL, et al. Serum myeloperoxidase levels are associated with the future risk of coronary artery disease in apparently healthy individuals: the EPIC-Norfolk prospective population study. J AM Coll Cardiol 2007; 50:159–165. 102. Wang TJ, Larson MG, Levy D, et al. Impact of age and sex on plasma natriuretic peptides levels in healthy adults. Am J Cardiol 2002; 90(3):254–258. 103. Wang JT, Larson MG, Levy D, et al. Plasma natriuretic peptides levels and the risk of cardiovascular events and death. N Engl J Med 2004; 350(7):655–663. 104. Sabatine OT, Jablonski KA, Omland T, et al. Prognostic value of B-type natriuretic peptides in patients with stable coronary artery disease: the PEACE Trial. J Am Coll Cardiol 2007; 50:205–214.

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Diagnosis of Coronary Heart Disease in the Elderly Wilbert S. Aronow Divisions of Cardiology, Geriatrics, and Pulmonary/Critical Care, Department of Medicine, New York Medical College, Valhalla, New York, U.S.A.

Jerome L. Fleg Division of Cardiovascular Diseases, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, U.S.A.

INTRODUCTION Coronary atherosclerosis is very common in the elderly population, with autopsy studies demonstrating a prevalence of at least 70% in persons over age 70 (1,2). These autopsy findings may be coincidental, with the disease clinically silent throughout the person’s life; however, only 15–30% of persons over age 65 show clinical manifestations of coronary heart disease (CHD). In the National Health and Nutrition Examination Survey (NHANES) 1999–2002, the prevalence of clinical CHD rose progressively with age, reaching 18.6% in men and 16.1% in women aged 75 years and above (3). Clinical CHD was present in 502 of 1160 men (43%) of mean age 80 years, and in 1019 of 2464 women (41%), of mean age 81 years in a long-term care facility (4). The marked discrepancy between the clinical and autopsy prevalence of CHD in the elderly indicates that CHD is often silent in this age group. Studies employing exercise testing and myocardial perfusion imaging in asymptomatic volunteers have demonstrated a striking age-related increase in silent myocardial ischemia, helping to reconcile differences in CHD prevalence between clinical and autopsy studies (5). Unfortunately, even though CHD is so prevalent in elderly persons, the disease is often undiagnosed or misdiagnosed in this age group. Failure to correctly diagnose the disease in the elderly may be due to a difference in clinical manifestations in this age group compared with that of younger patients. Such differences may reflect a difference in the disease process between older and younger patients, or it may be related to the superimposition of normal aging changes on those of concomitant diseases that may mask the usual clinical manifestations.

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Figure 1 Relative risks of coronary heart disease (CHD) events (top panel) and cardiovascular (CVD) events (bottom panel) in older volunteers by coronary artery calcium score and Framingham risk categories. Source: From Ref. 8.

Prevalence and extent of CHD increase with age. In the Coronary Artery Surgery Study, the prevalence of three-vessel CHD was 61% in patients aged 65 years and older versus 46% in those younger than 65 years; left main coronary artery stenosis was seen in 13% versus 9%, respectively (6). In a database of 21,573 patients undergoing cardiac catheterization between 1995 and 1998, left main coronary artery disease (CAD) increased in prevalence from 6.3% below age 70 to 13.9% in those 80 years and older (7). Multiple studies of patients undergoing percutaneous coronary interventions have also found higher prevalence of multivessel and left main disease in the elderly. Coronary artery calcium is also more common in the elderly than in younger populations. In the community-based Rotterdam Study, 1795 volunteers (mean age 71 years) with no history of CHD underwent electron beam computed tomography to detect coronary artery calcium (8). Calcium scores greater than 100 were observed in 49% and scores greater than 400 in 25%, both markedly higher than in younger populations. In this study, scores of 401 to 1000 were associated with a fourfold risk of hard CHD events compared with those with scores less than or equal to 100 even after adjustment for standard CHD risk factors; scores greater than 1000 increased CHD risk more than eightfold (Fig. 1) (8). Thus, coronary artery calcium is highly prevalent in older volunteers free of clinical CHD and has similar adverse prognostic significance as in younger populations. MYOCARDIAL ISCHEMIA Exertional angina pectoris caused by myocardial ischemia is commonly the first manifestation of CHD in young and middle-aged persons. It is usually easily recognized because of its typical features; however, in the elderly, this may not be the case. Because

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of limited physical activity, many elderly persons with CHD will not experience exertional angina pectoris. Even when angina pectoris does occur, the patient and physician may often attribute it to a cause other than CHD. For example, myocardial ischemia, appearing as shoulder or back pain, may be misdiagnosed as degenerative joint disease or, if the pain is located in the epigastric area, it may be ascribed to peptic ulcer disease. Nocturnal or postprandial epigastric discomfort of a burning quality is often attributed to hiatus hernia or esophageal reflux instead of CHD. Postprandial angina pectoris tends to occur among elderly and hypertensive patients with severe CHD and a markedly reduced ischemic threshold (9). Furthermore, the presence of comorbid conditions, so frequent in the elderly patient, adds to the confusion and may lead to misdiagnosis of the patient’s symptoms, which are actually due to myocardial ischemia. Instead of typical angina pectoris, myocardial ischemia in elderly patients is commonly manifested as dyspnea, which is referred to as an “angina equivalent.” Usually the dyspnea is exertional and is thought to be related to a transient rise in left ventricular (LV) end-diastolic pressure caused by ischemia superimposed on reduced ventricular compliance. Reduction in LV compliance may reflect normal aging changes or, more likely, is caused by the presence of coexisting hypertension and LV hypertrophy, disorders commonly present in elderly patients. Not infrequently, the dyspnea will occur in combination with angina pectoris, although the angina may be mild and of little concern to the patient. In other elderly individuals, myocardial ischemia is manifested clinically as frank heart failure, with some patients presenting with acute pulmonary edema. Chest pain may not be present, although the myocardial ischemia is severe enough to produce a combination of diastolic and systolic LV dysfunction. Siegel and associates (10) reported on a group of elderly patients, mean age 69 years, with CHD in whom the disease manifested as acute pulmonary edema. The majority of patients were without angina pectoris, and many were without a prior history of CHD. Ninety percent, however, had a past history of hypertension, and their electrocardiogram (ECG) showed LV hypertrophy. Angiographically, the majority of patients had three-vessel CHD, although LV systolic function was only moderately depressed, with a mean LV ejection fraction of 43%. Over 60% of these patients underwent coronary bypass surgery or percutaneous transluminal angioplasty, and the long-term prognosis was excellent. Similar findings have been reported in other studies of acute pulmonary edema caused by CHD (11–15). Graham and Vetrovec (15) compared patients with CHD hospitalized with acute pulmonary edema with patients hospitalized with angina pectoris without heart failure. The patients with acute pulmonary edema were older and, as in Siegel’s study (10), most of the patients had preexisting hypertension. Three-vessel CHD was common in both groups, although angina pectoris was infrequent in patients with pulmonary edema. LV ejection fraction was more depressed in patients with pulmonary edema (42%) than in the angina pectoris group (59%). In another study, Kunis and associates (13) reported findings of a small group of elderly patients with CHD who had recurrent pulmonary edema that could not be prevented with medical therapy. Angiographic studies demonstrated three-vessel coronary disease with preserved LV systolic function. Only after undergoing coronary bypass surgery was the recurrent pulmonary edema prevented in these very elderly patients (13). Another subset of elderly patients with CHD who present with acute pulmonary edema will demonstrate mitral valvular regurgitation that may be secondary to papillary muscle ischemia. In a study of 40 patients with acute pulmonary edema who had CHD, Stone and associates (16) found that 67% of the patients demonstrated moderate to severe mitral regurgitation on Doppler echocardiographic examination. The mean age of the

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patients was 76 years. In the majority of patients (74%), a murmur of mitral regurgitation was not detected despite examination by multiple observers. The authors concluded that mitral valve regurgitation is not uncommon in elderly patients with CHD who present with acute LV failure and may contribute to the genesis of pulmonary edema. In addition to having more severe CHD than younger patients, the elderly who undergo coronary arteriography demonstrate greater clinical instability, CHD complications, and comorbidities. In 21,573 patients, unstable angina pectoris was the indication for arteriography in 38% of persons aged 80 years and above versus 28% in those younger than 70 years (7). A history of heart failure was present, respectively, in 31% versus 11% of patients. Furthermore, comorbidities such as cerebrovascular and peripheral vascular disease, and chronic obstructive lung disease were two to three times more common in the elderly (7). A single-center study by Tresch and associates (17) in a group of elderly patients (mean age 71 years) who underwent coronary arteriography showed similar findings. The initial manifestation in the majority of patients was unstable ischemic chest pain; 34% of the patients presented with an acute myocardial infarction. In 8% of these elderly patients, the initial manifestation was acute heart failure unassociated with an acute myocardial infarction. On cardiac catheterization, multivessel disease was common, although LV systolic function was often normal. Only 9% of the patient had an LV ejection fraction of less than 35%. In contrast, patients younger than 65 years more commonly sustained an acute myocardial infarction as the initial manifestation of CHD, were less likely to present with heart failure, and had less multivessel CHD (17). Cardiac arrhythmias, particularly complex ventricular arrhythmias, may be a manifestation of myocardial ischemia in elderly patients with CHD. In Tresch’s study (17), 14% of elderly patients had arrhythmias as the initial manifestation of CHD. Sudden death may be the initial manifestation of CHD in older adults; in Framingham volunteers, 65 to 94 years old, CHD was manifest as sudden death in 15% of men and 12% of women (18). Silent or asymptomatic myocardial ischemia is a common problem in elderly patients with CHD. Approximately 15% of the elderly patients in Tresch’s study (17) were asymptomatic, with myocardial ischemia detected by exercise stress testing during a preoperative evaluation. In a study of 185 nursing home patients with CHD, mean age 83 years, silent myocardial ischemia (SI) was detected by 24-hour ambulatory electrocardiography (AECG) in 34% (19). SI was detected by 24-hour AECG in 51 of 117 (44%) similar patients with CHD or hypertension and an abnormal LV ejection fraction (20). Hedblad et al. (21) detected SI by 24-hour AECG in 19 of 39 patients (49%) with CHD. The reason for the frequent absence of chest pain in elderly patients with CAD is unclear. Various speculations have included (1) mental deterioration with inability to verbalize a sensation of pain, (2) better myocardial collateral circulation related to gradual progressive coronary artery narrowing, and (3) a decreased sensitivity to pain because of aging changes. Ambepitiya and associates (22) recently investigated the issue of age-associated changes in pain perception by comparing the time delay between the onset of 1 mm of electrocardiographic ST-segment depression and the onset of angina pectoris during exercise stress testing. The mean delay was 49 seconds in patients aged 70 to 82 years compared with 30 seconds in patients aged 42 to 59 years. The reason for this delay in perception of myocardial ischemia in the elderly is unexplained. The authors postulated that the impairment is most likely multifactorial in origin, involving peripheral mechanisms such as changes in the myocardial autonomic nerve endings with blunting of the perception of ischemic pain, as well as changes in central mechanisms. Another theory has suggested that the increase in SI and infarction in elderly patients with CHD is related to increased levels of, or receptor sensitivity to,

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endogenous opioids (23). This explanation does not appear likely because studies have demonstrated a similar increase in response of b-endorphin levels to exercise in both elderly and younger patients (24), and animal studies show a decrease in opioid receptor responsivity with advancing age (25). MYOCARDIAL INFARCTION As with myocardial ischemia, some patients with myocardial infarction may be completely asymptomatic or the symptoms may be so vague that they are unrecognized by the patient or physician as an acute myocardial infarction. The Framingham Heart Study (26) found that, in the general population, approximately 25% of myocardial infarctions diagnosed by pathological Q-waves on ECG were clinically unrecognized and, of these, 48% were truly silent. The incidence increased with age, with 42% of infarctions clinically silent in men aged 75 to 84 years. In women, the proportion of unrecognized myocardial infarctions was greater than in men, but the incidence was unaffected by increasing age. Other studies (27–34) have also reported a high prevalence of silent or unrecognized myocardial infarction in elderly patients, with rates from 21% to 68% (Table 1). These studies also demonstrated that the incidence of new coronary events, including recurrent myocardial infarction, ventricular fibrillation, and sudden death, in patients with unrecognized myocardial infarction is similar to (26,31–33,35) or higher (34) than in patients with recognized myocardial infarction. Symptoms when present in elderly patients with an acute myocardial infarction may be extremely vague and, as with myocardial ischemia, the diagnosis may be easily missed. Numerous studies have demonstrated the atypical features and wide variability of symptoms in elderly patients with acute myocardial infarction (Table 2) (27–29,36–40). Rodstein (27) found that in 52 elderly patients with acute myocardial infarction, 31% had no symptoms, 29% had chest pain, and 38% had dyspnea, neurological symptoms, or gastrointestinal symptoms (Tables 1 and 2). Pathy (36) demonstrated in 387 elderly patients with acute myocardial infarction that 19% had chest pain, 56% had dyspnea, neurological, or gastrointestinal symptoms, 8% had sudden death, and 17% had other symptoms (Table 2). In 110 elderly patients with acute myocardial infarction, Aronow (29) showed that 21% had no symptoms, 22% had chest pain, 35% had dyspnea, 18% had neurological symptoms, and 4% had gastrointestinal symptoms (Tables 1 and 2). Table 1 Prevalence of Silent or Unrecognized Q-Wave MI in Elderly Patients Unrecognized MI Study (reference)

Age (yr)

Number

Percentage age

Rodstein (n ¼ 52) (27) Aronow et al. (n ¼ 115) (28) Aronow (n ¼ 110) (29) Kannel et al. (n ¼ 199 men) (26) Kannel et al. (n ¼ 162 women) (26) Muller et al. (n ¼ 46 men) (30) Muller et al. (n ¼ 67 women) (30) Nadelmann et al. (n ¼ 115) (31) Sigurdsson et al. (n ¼ 237) (32) Sheifer et al. (n ¼ 901) (33)

61–92 mean, 82 mean, 82 65–94 65–94 65–95 65–95 75–85 58–62 mean, 72

16 78 23 66 58 14 34 50 83 201

31 68 21 33 36 30 51 43 35 22

Abbreviation: MI, myocardial infarction.

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Table 2 Prevalence of Dyspnea, Chest Pain, Neurological Symptoms, and Gastrointestinal Symptoms Associated with Acute MI in Elderly Patients Study (reference)

Age (yr)

Rodstein (n ¼ 52) (27) Pathy (n ¼ 387) (36) Tinker (n ¼ 87) (37) Bayer et al. (n ¼ 777) (38) Aronow (n ¼ 110) (29) Wroblewski (n ¼ 96) (39)

61–92 65 mean, 74 65–100 mean, 82 mean, 84

Dyspnea 10 77 19 329 38 57

(19%) (20%) (22%) (42%) (35%) (59%)

Chest pain

Neurological symptoms

GI symptoms

15 (29%) 75 (19%) 51 (59%) 515 (66%) 24 (22%) 19 (20%)

7 (13%) 126 (33%) 14 (16%) 232 (30%) 20 (18%) 33 (34%)

3 (6%) 10 (3%) 0 (0%) 145 (19%) 5 (4%) 24 (25%)

Abbreviations: MI, myocardial infarction; GI, gastrointestinal.

Other studies have also shown a high prevalence of dyspnea and neurological symptoms in elderly patients with acute myocardial infarction (37–39). In these studies, dyspnea was present in 22% of 87 patients (37), 42% of 777 patients (38), and 57% of 96 patients (39). Neurological symptoms were present in 16% (37), 30% (38), and 34% (39) of patients, respectively. In 777 elderly patients with acute myocardial infarction, Bayer and associates (38) reported that, with increasing age, the prevalence of chest pain decreased whereas the prevalence of dyspnea increased. In the Multicenter Chest Pain Study, the clinical presentation of acute myocardial infarction was compared in 1615 patients older than 65 years to 5109 younger patients (41). Because of the decreased prevalence in elderly patients of some typical features of acute myocardial infarction present in younger patients, such as pressure-like chest pain, the initial symptoms and signs had a lower predictive value for diagnosing acute myocardial infarction in the older group (41). Other features that are different between elderly and younger patients with acute myocardial infarction, and which may modify the therapy, need to be emphasized. An important difference is that elderly patients delay longer in seeking medical assistance after the onset of chest pain (42–44). In a study of out-of-hospital chest pain, Tresch and associates (42) reported that elderly patients, 80 years or older, delayed greater than 6.5 hours in calling paramedics, compared with a 3.9 hours delay in patients younger than 70 years. Interestingly, this prolonged delay occurred even though more than 50% of the elderly patients had a past history of either a myocardial infarction or coronary bypass surgery. Such delay may be one of the reasons why elderly patients with acute myocardial infarction are less likely to receive thrombolytic therapy or primary coronary angioplasty compared with younger patients. Sheifer et al. (44) showed in the Cooperative Cardiovascular Project that among 102,339 patients older than 65 years with confirmed acute myocardial infarction, 29.4% arrived at the hospital 6 hours or later after onset of the symptom. Another important age difference found in Tresch’s study (42), which has been reported in other studies (45,46), was the greater incidence of non-Q-wave myocardial infarctions in the elderly; 40% of elderly patients with acute myocardial infarction demonstrated non-Q-wave infarction compared with only 20% of the younger patients with infarction. Of 91 consecutive patients aged 70 years and older, mean age 78 years, with acute myocardial infarction, 61 (75%) had non-Q-wave myocardial infarction (46). In younger patients, non-Q-wave myocardial infarctions are usually associated with a more benign acute hospital course than Q-wave myocardial infarctions, although this does not pertain to elderly patients. Chung and associates (47) reported a10% hospital

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mortality and 36% one-year mortality in a group of elderly patients sustaining acute nonQ-wave myocardial infarction. In contrast, the acute hospital and one-year mortality in younger patients was 3% and 16%, respectively. Moreover, 23% of the elderly patients with non-Q-wave myocardial infarction developed atrial fibrillation, and 53% had congestive heart failure. Regardless of the type of myocardial infarction, elderly patients with acute myocardial infarction usually demonstrate more LV dysfunction than younger patients upon hospital admission and have a more complicated hospital course. Complications are common in elderly patients (48) including heart failure, ventricular rupture, shock, and death; and, not infrequently, the elderly patient’s initial complaints will reflect these complications instead of chest pain. Fedullo and Swinburne (49) compared complications from acute myocardial infarction in 104 patients aged 70 years and older with 157 patients 70 years or younger. Mortality was 22% in the older group versus 5% in the younger group. Cardiogenic shock occurred in 7% of the older group versus 1% of the younger group. Pulmonary edema occurred in 18% of the older group versus 4% of the younger group. Heart failure occurred in 29% of the older group versus 14% of the younger group. A rhythm disturbance requiring pacemaker implantation occurred in 5% of the older group versus 2% of the younger group (49). The increased mortality and complication rates in older patients with acute myocardial infarction suggest that an aggressive diagnostic and therapeutic approach may be beneficial in these patients (48). More aggressive therapy, including use of aspirin, b-blockers, angiotensin-converting enzyme inhibitors, statins, thrombolytic therapy, and coronary revascularization by percutaneous transluminal coronary angioplasty or by coronary bypass surgery, should be considered (see chap. 11). DIAGNOSTIC TECHNIQUES Resting ECG In addition to diagnosing recent or previous myocardial infarction, the resting ECG may show ischemic ST-segment depression, arrhythmias, conduction defects, and LV hypertrophy that are related to subsequent coronary events. At 37-month mean followup, elderly institutionalized patients with ischemic ST-segment depression 1 mm or greater on the resting ECG were 3.1 times more likely to develop new coronary events (myocardial infarction, primary ventricular fibrillation, or sudden cardiac death) than were those with no significant ST-segment depression (50). In this population, patients with ischemic ST-segment depression 0.5 to 0.9 mm on the resting ECG were 1.9 times more likely to develop new coronary events during the 37-month follow-up than were those with no significant ST-segment depression (50). At 45-month mean follow-up, pacemaker rhythm, atrial fibrillation, premature ventricular complexes, left bundle branch block, intraventricular conduction defect, and type II second-degree atrioventricular (AV) block were all associated with a higher incidence of new coronary events in such elderly patients (51). Numerous studies have documented that older adults with ECG LV hypertrophy have an increased incidence of new cardiovascular events. Men and women 65 to 94 years of age participating in the Framingham Heart Study who had ECG LV hypertrophy had an increased incidence of new coronary events, atherothrombotic brain infarction, chronic heart failure (CHF), and peripheral arterial disease compared with persons without ECG LV hypertrophy (52). Aronow and associates (53,54) also found that elderly patients with hypertension or CHD and ECG LV hypertrophy had an increased incidence of new coronary events, atherothrombotic brain infarction, and heart failure.

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Ambulatory Electrocardiography Multiple studies have demonstrated that complex ventricular arrhythmias in older adults without underlying cardiovascular disease are not associated with an increased incidence of new coronary events (Table 3) (55–60). In contrast, complex ventricular arrhythmias in elderly persons with underlying cardiovascular disease are associated with an increased incidence of new coronary events, including sudden cardiac death (Table 3) (57–60). The incidence of new coronary events is especially increased in elderly patients with complex ventricular arrhythmias and abnormal LV ejection fraction (58) or LV hypertrophy (59). Complex ventricular arrhythmias detected by 24-hour AECG in elderly nursing home patients with heart disease predicted a 2.5 times greater incidence of new coronary events at a two-year follow-up in persons with normal LV ejection fraction and 7.6 times greater incidence in those with abnormal LV ejection fraction (Table 3) (60). In elderly persons with heart disease, nonsustained ventricular tachycardia detected by 24-hour AECG was associated with a 3.2 times increased incidence of new coronary events at a two-year follow-up in persons with normal LV ejection fraction, and 6.8-fold higher incidence in those with abnormal LV ejection fraction (Table 3) (59). Those with heart disease, normal LV mass, and complex ventricular arrhythmias detected by 24-hour AECG experienced a 2.4-fold greater incidence of primary ventricular fibrillation or sudden cardiac death at a 27-month follow-up than those without such arrhythmias. This risk was 7.3 times higher in persons with both complex ventricular arrhythmias and echocardiographic LV hypertrophy (Table 3) (60). AECG performed for 24 hour is also useful in detecting myocardial ischemia in elderly persons with suspected CHD who cannot perform treadmill or bicycle exercise stress testing because of advanced age, intermittent claudication, musculoskeletal disorders, heart failure, or pulmonary disease. Ischemic ST-segment changes demonstrated on the 24-hour AECG correlate with transient abnormalities in myocardial perfusion and LV systolic dysfunction. The changes may be associated with symptoms, or symptoms may be completely absent, which is referred to as SI. SI is predictive of future coronary events, including cardiovascular mortality in older persons with CHD (19–21,62–66) and in those with no clinical heart disease (21,55,67) (Table 4). The incidence of new coronary events is especially increased in elderly individuals with SI plus complex ventricular arrhythmias (62), abnormal LV ejection fraction (20), or echocardiographic LV hypertrophy (68). In a population of institutionalized elderly with CHD or hypertension, at a 40-month follow-up, SI predicted a doubled incidence of new coronary events in persons with normal LV ejection fraction and a 3.2-fold increase in those with abnormal LV ejection fraction (Table 4) (20). The combination of complex ventricular arrhythmias plus SI was associated with a fourfold higher incidence of new coronary events (Table 4) (20); echocardiographic LV hypertrophy plus SI predicted a 3.4-fold greater incidence of new coronary events at a 31-month follow-up (68). SI was associated with approximately a doubled incidence of new coronary events over nearly four years of follow-up in both elderly men and women with CHD, hypertension, valvular heart disease, or cardiomyopathy. Among those without clinical heart disease, SI predicted an incidence of new coronary events 6.3-fold higher in men and 4.4-fold higher in women (Table 4) (67). Hedblad and associates (21) showed at a 43-month follow-up that SI predicted a 16-fold higher incidence of new coronary events in men with CHD and a 4.4-fold higher event rate in men without CHD (Table 4). Fleg and associates (55) showed at a 10-year follow-up of elderly persons without heart disease that SI was associated with a 3.8-fold

CAD HT, VD, or CMP No heart disease CAD HT, VD, or CMP No heart disease

No heart disease Heart disease

No heart disease No heart disease Heart disease Heart disease

Cardiac status

45 45 45 47 47 47

60 27

120 29 39 24

Follow-up (mo)

No association No association Increased 1.7 times by complex VA With normal LVEF, increased 2.5 times by complex VA and 3.2 times by VT; increased 7.6 times by complex VA plus abnormal LVEF and increased 6.8 times by VT plus abnormal LVEF Total mortality increased 1.9 times by frequent VA With no LVH, SCD or VF increased 2.4 times by complex VA and 1.8 times by VT; SCD or VF increased 7.3 times by complex VA plus LVH and increased 7.1 times by VT plus LVH Increased 2.4 times by complex VA and 1.7 times by VT Increased 1.9 times by complex VA and 1.9 times by VT No association Increased 2.5 times by complex VA and 1.7 times by VT Increased 2.2 times by complex VA and 2.0 times by VT No association

Incidence of new coronary events

Abbreviations: VA, ventricular arrhythmias; VT, ventricular tachycardia; LVEF, left ventricular ejection fraction; LVH, left ventricular hypertrophy; SCD, sudden coronary death; VF, primary ventricular fibrillation; CAD, coronary artery disease; HT, hypertension; VD, valvular heart disease; CMP, cardiomyopathy.

80 80 80 81 81 81

75–95 82

Martin et al. (n ¼ 106) (57) Aronow et al. (n ¼ 468) (60)

Aronow et al. (n ¼ 395 men) (61) Aronow et al. (n ¼ 385 men) (61) Aronow et al. (n ¼ 135 men) (61) Aronow et al. (n ¼ 771 women) (61) Aronow et al. (n ¼ 806 women) (61) Aronow et al. (n ¼ 297 women) (61)

69 79 82 82

Mean age (yr)

Fleg et al. (n ¼ 98) (55) Kirkland et al. (n ¼ 30) (56) Aronow et al. (n ¼ 843) (58) Aronow et al. (n ¼ 391) (59)

Study (reference)

Table 3 Association of Complex Ventricular Arrhythmias and Ventricular Tachycardia with New Coronary Events in Elderly Patients

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CAD No CAD CAD HT, VD, or CMP No heart disease CAD HT, VD, or CMP No heart disease

68 68 80 80 80 81 81 81

Hedblad et al. (n ¼ 39 men) (21) Hedblad et al. (n ¼ 385 men) (21) Aronow et al. (n ¼ 395 men) (67) Aronow et al. (n ¼ 385 men) (67) Aronow et al. (n ¼ 135 men) (67) Aronow et al. (n ¼ 771 women) (67) Aronow et al. (n ¼ 806 women) (67) Aronow et al. (n ¼ 297 women) (67) 47

47

43 43 45 45 45 47

37

120 40

Follow-up (mo)

Increased 4.4 times by SI

Increased 1.7 times by SI

Increased 3.8 times by SI Increased 2.0 times by SI; increased 2.4 times by SI with normal LVEF; increased 3.2 times by SI with abnormal LVEF Increased 2.0 times by SI; increased 4.0 times by SI plus complex VA; increased 2.5 times by SI plus VT Increased 16.0 times by SI Increased 4.4 times by SI Increased 2.1 times by SI Increased 1.8 times by SI Increased 6.3 times by SI Increased 2.1 times by SI

Incidence of new coronary events

252

Abbreviations: SI, silent myocardial ischemia; CAD, coronary artery disease; HT, hypertension; LVEF, left ventricular ejection fraction; VA, ventricular arrhythmias; VT, ventricular tachycardia; VD, valvular heart disease; CMP, cardiomyopathy.

CAD or HT

82

Aronow et al. (n ¼ 404) (62)

No heart disease CAD or HT

Cardiac status

69 82

Mean age (yr)

Fleg et al. (n ¼ 98) (55) Aronow et al. (n ¼ 393) (20)

Study (reference)

Table 4 Association of SI with New Coronary Events in Elderly Patients

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increased incidence of new coronary events (Table 4); two of the three persons who died suddenly had evidence of SI plus ventricular tachycardia detected by 24-hour AECG. SI detected by 24-hour AECG has been used in the assessment of patients undergoing nocardiac surgery. Such use of 24-hour AECG may be especially beneficial in elderly persons, who are frequently at high surgical risk and may not be able to undergo preoperative exercise stress testing because of concomitant illness. No study, however, has shown SI detected by 24-hour AECG to be more accurate than pharmacological stress testing in stratifying preoperative elderly patients into high- and low-risk groups. Raby and associates (69) studied 176 patients who underwent 24-hour AECG before noncardiac surgery. Eighteen percent of the patients had signs of myocardial ischemia on their preoperative 24-hour AECG, with the ischemia silent in the majority of patients. Preoperative myocardial ischemia was highly predictive of postoperative cardiac events. The sensitivity of preoperative myocardial ischemia for postoperative cardiac events in this study was 92%, the specificity 88%, the positive predictive value 38%, and the negative predictive value 99% (69). Multivariate analysis showed preoperative myocardial ischemia to be the most significant variable correlating with postoperative cardiac events. The authors concluded that the absence of preoperative myocardial ischemia on the 24-hour AECG indicates a very low risk for postoperative cardiac events. Thirty-eight percent of the patients in this study were older than 69 years, and preoperative myocardial ischemia was more prevalent in these elderly patients compared with the younger patients. In a follow-up study, Raby and associates (70) assessed the significance of intraoperative and postoperative SI in addition to preoperative ischemia detected on a 24hour AECG in relationship to postoperative cardiac events in patients undergoing peripheral vascular surgery. The mean age of the patients in this study was 67 years, and 37% were 70 years or older. As in their previous study, the investigators found preoperative SI to be the most important predictor of postoperative cardiac events. Preoperative myocardial ischemia also strongly correlated with intraoperative and postoperative ischemia, and perioperative myocardial ischemia commonly preceded clinical cardiac events (70).

Signal-averaged Electrocardiography Signal-averaged electrocardiography (SAECG) was performed in 121 elderly postinfarction patients with asymptomatic complex ventricular arrhythmias detected by 24hour AECG and a LV ejection fraction greater than or equal to 40% (71). At 29-month follow-up, the sensitivity, specificity, positive predictive value, and negative predictive value for predicting sudden cardiac death were 52%, 68%, 32%, and 83%, respectively, for a positive SAECG; 63%, 70%, 38%, and 87%, respectively, for nonsustained ventricular tachycardia; and 26%, 89%, 41%, and 81%, respectively, for a positive SAECG plus nonsustained ventricular tachycardia (71).

Echocardiography Echocardiography is useful in detecting regional LV wall motion abnormalities, acute myocardial ischemia, and complications secondary to acute myocardial infarction, LV aneurysm, cardiac thrombi, left main CAD, LV hypertrophy, and associated valvular heart disease. Echocardiography is useful in evaluating LV function and cardiac chamber size in elderly persons with CHD. Echocardiographic LV ejection fraction is also important in predicting new coronary events in elderly persons with CHD (20,59,72).

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New coronary events developed at a two-year follow-up in 30 of 45 elderly nursing home patients with CHD and abnormal LV ejection fraction (<50%) and in 24 of 90 such patients with CHD and normal LV ejection fraction (relative risk ¼ 2.5) (59). In this population of older adults with CHD and heart failure, cardiovascular mortality is higher among individuals with abnormal than those with normal LV ejection fraction (72,73). Multivariate analysis showed that LV ejection fraction was the most important prognostic variable for mortality in elderly persons with CHF associated with CHD; those with abnormal LV ejection fraction had approximately twice the mortality of persons with normal LV ejection fraction (72,73). Numerous studies have demonstrated that elderly patients with echocardiographic LV hypertrophy have an increased incidence of new cardiovascular events (53,54,60,68,74,75). At four-year follow-up, elderly men and women in the Framingham Study with echocardiographic LV hypertrophy had a relative risk for new coronary events of 1.67 for men and of 1.60 for women per 50 g/m increase in LV mass/height (Table 5) (74). In these volunteers, echocardiographic LV hypertrophy was 15.3 times more sensitive than ECG LV hypertrophy in predicting new coronary events in elderly men and 4.3 times more sensitive than ECG LV hypertrophy in predicting new coronary events in elderly women (74). Over 27 months of follow-up, institutionalized elderly adults with echocardiographic LV hypertrophy developed a 2.7-fold higher incidence of new coronary events, 3.7-fold higher rate of new atherothrombotic brain infarction (ABI), and 3.3-fold greater rate of primary ventricular fibrillation or cardiac death (Table 5) (60). At a 37-month follow-up of elderly persons with CHD or hypertension, echocardiographic LV hypertrophy predicted a doubled incidence of new coronary events and a 2.8-fold greater rate of new ABI (Table 5) (53). Echocardiographic LV hypertrophy was approximately four times more sensitive than ECG LV hypertrophy in predicting new coronary events or new ABI in this population (53). Multiple logistic regression analysis showed that echocardiographic Table 5 Association of Echocardiographic LVH with New Cardiovascular Events in Elderly Persons Mean age (yr)

Followup (yr)

Framingham Study (n ¼ 406 men) (74) Framingham Study (n ¼ 735 women) (74) Cardiovascular disease (n ¼ 557) (75) Hypertension or CHD (n ¼ 360) (59) Heart disease (n ¼ 468) (60)

65–94

4

65–94

4

82

2.3

82

3.1

82

2.3

African-Americans with hypertension (n ¼ 84) (54) Whites with hypertension (n ¼ 326) (54)

78

3.1

82

3.6

Population (reference)

Incidence of new cardiovascular events Coronary events increased 1.67 times per 50 g/m increase in LV mass/height Coronary events increased 1.60 times per 50 g/m increase in LV mass/height LVH increased coronary events 2.7 times and ABI 3.7 times LVH increased coronary events 2.0 times and ABI 2.8 times LVH increased primary ventricular fibrillation or sudden cardiac death 3.3 times LV increased coronary events 3.3 times, ABI 2.8 times, and CHF 3.7 times LV increased coronary events 2.7 times, ABI 3.3 times, and CHF 3.5 times

Abbreviations: LVH, left ventricular hypertrophy; CHD, coronary heart disease; ABI, atherothrombotic brain infarction; CHF, chronic heart failure.

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LV hypertrophy was a strong independent risk factor in such a population for new coronary events (odds ratio of 3.2), new ABI (odds ratio of 4.2), and new CHF (odds ratio of 2.6) (54); increased risk was similar in African-Americans and whites (Table 5). Exercise and Pharmacological Stress Testing Although age per se significantly influences the cardiovascular response to aerobic exercise, treadmill or cycle ergometer exercise testing remains a useful diagnostic and prognostic tool for evaluating older patients with suspected or documented CHD. Exercise ECG is also a useful prognostic indicator of subsequent coronary events in patients with documented CHD, with or without previous myocardial infarction. Exercise testing in elderly patients should evaluate symptoms that develop during exercise (especially angina pectoris or dyspnea, which may be an anginal equivalent), the maximal workload achieved, the heart rate and blood pressure response, the presence, magnitude, and onset time of ischemic ST-segment depression or elevation, and the presence of exercise-induced arrhythmias. These variables must be interpreted in light of normative age-associated changes including a decline of maximal aerobic capacity averaging 8% to 10% per decade (76,77), a reduced maximal heart rate of approximately 1 beat/min/yr, and an exaggerated rise in systolic blood pressure (78,79). Maximal LV systolic emptying is impaired in older adults, resulting in a higher end-systolic volume and lower ejection fraction compared with younger individuals (78–80); stroke volume is preserved, however, by a greater reliance on the Frank-Starling mechanism to augment LV enddiastolic volume (79,80). Exercise-induced supraventricular (81) and ventricular arrhythmias (82) both increase exponentially with age in clinically healthy volunteers but do not increase the risk for future CHD events in such a population. Given the cardiovascular and noncardiovascular limitations to exercise in older adults, exercise-testing protocols should employ low starting work rates and smaller work increments than in younger patients. Thus, protocols such as the Naughton or Balke, in which the speed is held constant and only the elevation is increased, are ideal for the elderly. Individuals with gait disturbances can often be tested on a cycle ergometer, although their aerobic capacity and peak heart rate are usually lower than those achieved with treadmill exercise. Diagnostic sensitivity of the exercise ECG for CHD appears to increase with age at the expense of a modest reduction in specificity. Hlatky et al. (83) found the exercise ECG to have a sensitivity of 84% and a specificity of 70% for the diagnosis of CHD in patients 60 years or older. In contrast, sensitivity was only 56% in patients younger than 40 years, although specificity was 84%. In patients aged 65 years and older, Newman and Phillips (84) found a sensitivity of 85%, a specificity of 56%, and a positive predictive value of 86% for the exercise ECG in diagnosing CHD. The increased sensitivity and high positive predictive value of the exercise ECG with increasing age found in these two treadmill exercise studies was probably due to the increased prevalence and severity of CHD in elderly persons (85). Reduced specificity is largely explained by a higher prevalence of ST-T-wave abnormalities on the pre-exercise ECG. Prognostic Utility of the Exercise ECG Numerous studies in patients with known or suspected CHD have shown that the standard treadmill exercise test provides valuable prognostic information. In a sample of 2632 patients 65 years or older undergoing clinically indicated exercise testing, a lower peak treadmill workload was a strong independent predictor of cardiac death

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over the subsequent 2.9-year mean follow-up period (86). Of note, neither ischemic ST changes nor angina were predictive. In a similar population, however, Glover et al., demonstrated that an ischemic ST-segment response to exercise predicted an eightfold cardiovascular mortality (17% vs. 2%) over a two-year follow-up (87). The Duke treadmill score, which incorporates exercise duration, magnitude of ischemic ST-segment depression, and presence of exercise-induced angina, has demonstrated prognostic utility in younger populations (88,89), but appears to be less useful in patients aged 75 years or older (89). Exercise testing after myocardial infarction has prognostic value in older patients, as it does in younger ones. Identification of jeopardized myocardium in such postmyocardial infarction patients may be useful because recurrent infarction and sudden cardiac death are the most common causes of one-year mortality posthospital discharge (90). In 188 patients aged 70 years or older who underwent exercise testing a mean of 14 days’ postinfarction, Ciaroni et al. (91) found that a rise in systolic blood pressure of less than 30 mmHg, a maximal cycle workrate less than 60 W, and an exercise duration less than 5 minutes predicted cardiovascular death; whereas ST-segment depression and ventricular arrhythmias predicted reinfarction and the need for coronary revascularization. Similar to the general postinfarction population, older patients excluded from exercise testing after myocardial infarction have the highest cardiovascular risk. For example, Deckers et al. (92) found a mortality of 4% for patients 65 years or older who were able to perform a cycle exercise test postinfarction versus a mortality of 37% for those excluded. Although the diagnostic and prognostic utility of exercise testing in general population is modest, such testing may have greater value in asymptomatic older persons with multiple CHD risks factors (93). Older subjects embarking on a vigorous training program or those entrusted with the safety of others, such as school bus drivers, are appropriate candidates for testing. Exercise Cardiac Imaging Exercise stress testing incorporating thallium perfusion scintigraphy, radionuclide ventriculography, or echocardiography provides additional value in the diagnosis and prognosis of CHD compared with the exercise ECG alone. Iskandrian et al. (94) showed that exercise thallium-201 imaging can be used for risk stratification of elderly patients with CHD. The risk for cardiac death or nonfatal myocardial infarction at a 25-month follow-up in 449 patients 60 years or older was less than 1% in patients with normal images, 5% in patients with single-vessel thallium-201 abnormality, and 13% in patients with multivessel thallium-201 abnormality. In 120 patients 70 years or older with known or suspected CHD who underwent exercise thallium-201 scintigraphy, Hilton et al. (95) showed that the combination of low peak exercise capacity and any thallium-201 perfusion defect was the most powerful predictor of new cardiac events (relative risk, 5.3 at 1 year). Individuals with an ischemic ST-segment depression more than 2 mm and a thallium defect who failed to complete stage 1 of a Bruce protocol suffered a 47% event rate. Exercise single-photon emission computed tomography (SPECT) was performed in 247 elderly patients aged 75 years and older (108 women and 139 men) and classified 49% of the patients as low risk and 35% of the patients as high risk by a summed stress score (96). At 6.4-year follow-up, patients classified as low risk had an annual cardiac mortality rate of 0.8%, and those classified as high risk had an annual cardiac mortality rate of 5.8%. In this study, the Duke treadmill score was not significantly associated with cardiac death (96).

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Fleg et al. (5) performed maximal treadmill exercise ECGs and thallium scintigraphy in 407 asymptomatic volunteers aged between 40 to 96 years from the Baltimore Longitudinal Study on Aging. At 4.6 years of follow-up, new cardiac events developed in 7% of patients who had negative results on both tests, 8% of patients with a single positive result, and 48% of patients with both results positive. Persons with both a positive exercise ECG and a thallium perfusion defect averaged 69 years of age and had 3.6 times the relative risk for new coronary events as those with negative results, independent of standard coronary risk factors (5). Echocardiography during, or more commonly, immediately after treadmill or cycle exercise has also proven useful in the detection and prognostication of CHD. Overall sensitivity of exercise-induced wall motion abnormalities for CHD using this technique is 74–97% with specificity of 64–88%, similar to values of exercise thallium scintigraphy (97,98). As with other diagnostic modalities, the sensitivity of exercise echocardiography increases with the extent of CHD, which should result in a high sensitivity in the elderly. Although a lower technical success of echocardiographic imaging in older versus younger patients is probably responsible for a lesser utilization of exercise echocardiography in the elderly, recent advances in echocardiographic equipment have largely overcome this deficiency. In 2632 patients, aged 65 years or older, referred for clinically indicated exercise echocardiography, the exercise-induced changes in LV end-systolic volume and the exercise LV ejection fraction or wall motion score were predictors of cardiac events and cardiac death, independent of clinical status, resting echocardiography, and exercise duration (86) (Fig. 2). At 2.8-year follow-up of 1268 patients of mean age 60 years, nonfatal myocardial infarction or cardiac death occurred in 1.1% patients per year with a normal stress echocardiogram and in 3.6% patients per year with a normal stress ECG ( p < 0.001) (99). Peak wall motion score index (hazard ratio ¼ 2.55) and LV ejection fraction (hazard ratio ¼ 0.99) were independent and incremental prognostic markers for stress echocardiography (99).

Figure 2 Exercise echocardiographic wall motion score as a predictor of survival free of cardiac events in 2632 patients aged 65 years or older referred for exercise testing. A higher wall motion score index (WMSI) denotes worse LV function. Source: From Ref. 86.

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Older patients with diabetes mellitus (mean age 63 years) had a significantly higher prevalence of unrecognized myocardial infarction (18% of 287 patients) detected by a treadmill exercise sestamibi stress test than age-matched and gender-matched patients without diabetes mellitus (7% of 292 patients) ( p < 0.001) (100). Patients with diabetes mellitus also had a higher prevalence of SI without a history of angina pectoris (33%) than patients without diabetes mellitus (18%) (p < 0.001) (100). Pharmacological Stress Testing The greatest advancement in stress testing over the past decade has been the widespread application of pharmacological stress testing on populations unable to perform diagnostically adequate exercise tests. The elderly are clearly the greatest beneficiaries of pharmacological stress testing because of the high prevalence of exercise-limiting conditions among them, such as obstructive lung disease, peripheral arterial insufficiency, arthritis, and neuromuscular disorders. The agents most commonly used for this purpose are the vasodilators, dipyridamole and adenosine, and the synthetic catecholamine, dobutamine, in conjunction with either radionuclide or echocardiographic imaging. Dipyridamole is a phosphodiesterase inhibitor that blocks degradation of adenosine, thereby increasing plasma adenosine, which is a potent arteriolar dilator. Both dipyridamole and adenosine dilate normal coronary arteries more than stenotic vessels, creating a coronary steal that causes a myocardial perfusion defect or wall motion abnormality. With either drug, serious side effects, including bronchospasm, hypotension, and arrhythmias, occur in 2–3% of patients but do not appear to be age-related (101–103). In 101 subjects older than 70 years, the sensitivity and specificity of dipyridamole thallium imaging for CHD were 86% and 75%, respectively, compared with corresponding values of 83% and 70% in younger patients (102). In 92 patients aged 65 years and older who had undergone prior coronary artery bypass grafting, the dipyridamole sestamibi stress test had a sensitivity of 95%, a specificity of 50%, a positive predictive value of 96%, and a negative predictive value of 43% for graft occlusion or 50% or more new native CAD (108); these values were similar to those in younger patients (104). Prognostic utility of dipyridamole in combination with echocardiography was shown in 190 patients aged 65 years and above (mean, 68  3), evaluated at a mean of 10 days after uncomplicated myocardial infarction. Patients with a positive test experienced a threefold risk of future cardiac events and 4.4-fold risk of death compared with those with negative, i.e., normal results (105). An abnormal dipyridamole thallium scan was the best predictor of subsequent events in 348 patients aged 70 years and older with known or suspected CHD conferring a relative risk of 7.2 on multivariate analysis (106). Dipyridamole stress imaging has also been used to identify patients at high cardiovascular risk prior to vascular surgery. Hendel et al. (107) observed that a reversible thallium perfusion defect conferred a ninefold risk of perioperative myocardial infarction or cardiac death in 360 such patients whose mean age was 65 years. Adenosine echocardiography has also demonstrated both diagnostic and prognostic utility in older patients with known or suspected CHD. In 120 such patients 70 years or older, sensitivity for CHD was 66%, specificity 90%, and diagnostic accuracy 73% (103). Sensitivity increased from 42% in patients with single-vessel CHD to 73% in those with multivessel disease. An abnormal adenosine echocardiogram predicted a threefold risk of future cardiac events, independent of clinical CHD risk factors. The only serious effect was transient AV block, which occurred in 6% of patients, but was asymptomatic and self limited in all (103). In another study, the risk of such transient AV block after adenosine infusion was 18% in patients 75 years or older versus 8% in younger patients (108).

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Combining adenosine infusion with symptom-limited treadmill exercise reduced the incidence of premature infusion termination from 15% to 5%. A potential advantage of adenosine, and probably dipyridamole, stress testing over exercise is the ability to continue b-blockers without compromising on diagnostic yield. In a study of 158 consecutive patients (mean age 66 years) who had adenosine SPECT myocardial perfusion imaging, b-blocker therapy was continued through the test in 82 patients and stopped 48 hours prior to the test in 76 patients (109). b-Blocker therapy did not affect the extent, severity, and reversibility of perfusion defects on adenosine SPECT myocardial perfusion imaging. However, patients who stopped b-blockers for 48 hours had a higher incidence of angina pectoris (10%) than those who continued b-blocker therapy through the test (2%) (109). Dobutamine is a synthetic catecholamine that is frequently used as a pharmacological stressor in older patients, in combination with echocardiography or thallium imaging. Dobutamine produces dose-related increases in heart rate and inotropy that augment coronary artery blood flow, thereby inducing ischemia by a mechanism similar to exercise in patients with CHD. Atropine is frequently combined with dobutamine to help insure an adequate chronotropic response. The classic ischemic response induced by dobutamine is characterized by improved wall motion at low doses but worsening wall motion at high doses. Dobutamine is particularly useful in older patients with obstructive lung disease, in whom both dipyridamole and adenosine are contraindicated. In 120 patients aged 70 years or older with known or suspected CHD, dobutamine echocardiography had a sensitivity of 87%, a specificity of 84%, and an accuracy of 86%, all higher than corresponding figures for adenosine in the same patients (Table 6) (103). Patients with a positive dobutamine stress test had a 7.3-fold risk for a future cardiac event compared with those with a normal test. Dobutamine thallium scintigraphy demonstrated sensitivity of 86% and specificity of 90% in 144 patients aged 65  10 years (110), numbers very similar to the echocardiographic data with this drug. Dobutamine has also been used to predict perioperative coronary events in older patients undergoing vascular surgery (111). Although dobutamine is generally well tolerated in all age groups, higher rates of asymptomatic hypotension and both supraventricular and ventricular arrhythmias, but a lower rate of chest pain, were reported in patients older versus younger than 70 years (112,113). Several large series have confirmed the prognostic value of dobutamine stress testing. At 6.5-year follow-up of 1434 patients older than 65 years who had dobutamine stress echocardiography, resting wall abnormalities (hazard ratio ¼ 1.13) and inducible ischemia (hazard ratio ¼ 2.1) were significant independent predictors of

Table 6 Comparison of Dobutamine and Adenosine Echocardiography in Detection of CAD in Patients Aged 70 Years or Older

Sensitivity Overall 1-vessel CHD 2-vessel CHD 3-vessel CHD Specificity Accuracy

Dobutamine (%)

Adenosine (%)

p Value

87 74 88 91 84 86

66 42 76 71 90 73

<0.001 NS NS 0.02 NS 0.01

Abbreviations: CHD, coronary heart disease; NS, not significant. Source: Adapted from Ref. 97.

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cardiac death or nonfatal myocardial infarction (114). At 2.6-year follow-up of 7333 patients, mean age 59 years, who had stress echocardiography with either dipyridamole or dobutamine, the cardiac mortality was 29% in patients with a positive test versus 8% in those with a negative test (115). Older age remained a strong independent predictor of cardiac death. Among 931 patients (mean age 61 years) with inducible myocardial ischemia during dobutamine stress echocardiography, ischemia was silent in 69% and symptomatic in 31% (116). At 5.5-year follow-up, cardiac death or nonfatal myocardial infarction occurred in 3% of patients with symptomatic myocardial ischemia and in 4.6% of patients with SI ( p < 0.01). SI predicted a 70% higher risk of cardiac death or nonfatal myocardial infarction, perhaps because such patients were less likely to be treated with cardioprotective therapy and coronary revascularization than patients with symptomatic myocardial ischemia (116). Multislice Computed Tomography and Magnetic Resonance Imaging Over the past several years, multislice computed tomography (MSCT) and magnetic resonance imaging (MRI) have become increasingly used to detect CHD. Both techniques allow direct visualization of the coronary arteries rather than relying on their functional consequences. Since their introduction for coronary artery imaging in 2000, CT scanners have increased from 4 to 16 detectors and more recently to 64 detectors. Thus, new generation scanners acquire more imaging slices per rotation, allowing faster image acquisition and improved temporal and spatial resolution. As a result, these scanners require a shorter period of breath holding by the patient, allow a wider range of acceptable heart rates, and the ability to image very obese patients and those with moderate coronary artery calcium, using lower contrast volumes. All of these advances in CT imaging facilitate the imaging of older patients with suspected CHD. A recent meta-analysis of results with 4, 8, and 16 slice scanners revealed a per artery sensitivity of 85% and specificity of 95% (117). It should be noted, however, that the mean age of patients in the 24 studies included ranged from 56 to 65 years; no separate analyses were performed in the elderly. In another pooled analysis, MSCT detected occluded coronary artery bypass grafts with a sensitivity of 84% and a specificity of 95% (118). Artifacts from metal surgical clips remain an important limitation of MSCT for this use; approximately, only 80% of grafts can be evaluated. Significant drawbacks of MSCT are the contrast dye load and the radiation exposure, both similar to those from conventional coronary angiography. Cardiac MRI has also become an attractive method for noninvasive coronary artery imaging in recent years. This technique avoids the use of ionizing radiation and iodinated intravenous contrast material as well as the need for breath holding. Faster MRI techniques and more powerful magnets have improved the quality of coronary arterial images. A meta-analysis of 28 studies using MRI coronary angiography found a per-artery sensitivity of 72% and a specificity of 87%; 86% of the coronary arterial segments were assessable (117). However, the mean age of the patients in this analysis was 63 years, with only one very small study having a mean patient age over 65 years. As with MSCT, therefore, age-specific diagnostic accuracy is not available. Dewey et al. performed a direct comparison of MSCT with MRI for noninvasive coronary arteriography in 129 patients (mean age, 64 years) with suspected CHD (119). Sensitivity for coronary stenoses greater than 50% of lumimal diameter was 82% for MSCT versus 54% for MRI; the respective specificities were 90% and 87%. Negative predictive value was slightly higher for CT (95% vs. 90%). In this study, 74% of patients

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preferred MSCT to MRI. The greater diagnostic accuracy of MSCT over MRI in this study is consistent with the meta-analytic findings noted above. Thus, MSCT currently has a higher accuracy than MRI to detect or exclude significant CHD, although data specific to the elderly are lacking. As both techniques may miss significant coronary artery stenoses, they are best used in patients with a pretest probability of CHD less than 50%. In such patients, a normal coronary arteriogram by MSCT or MRI would reduce the posttest probability of CHD to less than 10%, avoiding the need for invasive coronary arteriography (119,120). Both techniques are thus attractive for use in emergency room settings in determining which low-to-intermediate risk patients presenting with acute chest pain should be admitted. Coronary Arteriography Despite the recent advances in noninvasive cardiac imaging discussed above, invasive coronary arteriography remains the accepted standard for detection and quantitation of CHD, although it may underestimate the extent of coronary atherosclerosis compared with intravascular ultrasound. Major complications of coronary arteriography include myocardial infarction, stroke, and death. In the Coronary Artery Surgery Study (CASS) registry, each of these endpoints was approximately three times as common in patients aged 65 and above than in younger individuals (6). A single center study between 1980 and 1990 in 242 patients 80 to 92 years old reported a mortality of 0.8% and nonfatal complication rate of 5%, compared with respective rates of 0.15% and 1.5% in patients younger than 80 years (121). The increased risk in the elderly is largely explained by their generally greater severity of underlying cardiac and noncardiac disease. Although major complication rates from cardiac catheterization and coronary arteriography continued to decline through the 1990s (122), the elderly should still be considered at higher risk, especially those aged 80 years and beyond. REFERENCES 1. White NK, Edwards JE, Dry TJ. The relationship of the degree of coronary atherosclerosis with age. Circulation 1950; 1:645–654. 2. Elveback L, Lie JT. Continued high prevalence of coronary artery disease at autopsy in Olmstead County, Minnesota, 1950 to 1970. Circulation 1984; 70:345–349. 3. Center for Disease Control and Prevention/National center for Health Statistics. National Health and Nutrition Examination Survey (NHANES) 1999–2002. 4. Aronow WS, Ahn C, Gutstein H. Prevalence and incidence of cardiovascular disease in 1160 older men and 2464 older women in a long-term health care facility. J Gerontol Med Sci 2002; 57A:M45–M46. 5. Fleg JL, Gerstenblith G, Zonderman AB, et al. Prevalence and prognostic significance of exercise-induced silent myocardial ischemia detected by thallium scintigraphy and electrocardigraphy in asymptomatic volunteers. Circulation 1990; 81(2):428–436. 6. Gersh BJ, Kronmal RA, Frye RL, et al. Coronary arteriography and coronary artery bypass surgery: Morbidity and mortality in patients ages 65 years or older. A report from the Coronary Artery Surgery Study. Circulation 1983; 67:483–491. 7. Graham MM, Ghali WA, Faris PD, et al. for the Alberta Provincial Project for Outcomes Assessment in Coronary Heart Disease Investigators. Survival after coronary revascularization in the elderly. Circulation 2002; 105:2378–2384. 8. Vliegenthart R, Oudkerk M, Hofman A, et al. Coronary calcification improves cardiovascular risk prediction in the elderly. Circulation 2005; 112:572–577.

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113. Hiro J, Hiro T, Reid CL, et al. Safety and results of dobutamine stress echocardiography in women versus men and in patients older and younger than 75 years of age. Am J Cardiol 1997; 80(8):1014–1020. 114. Sicari R, Pasanisi E, Venneri L, et al. Stress echo results predict mortality: a large-scale multicenter prospective international study. J Am Coll Cardiol 2003; 41:589–595. 115. Biagini E, Elhendy A, Schinkel AF, et al. Long-term prediction of mortality in elderly persons by dobutamine stress echocardiography. J Gerontol A Biol Sci Med Sci 2005; 60:1333–1338. 116. Biagini E, Schinkel AFL, Bax JJ, et al,. Long-term outcome in patients with silent versus symptomatic ischaemia during dobutamine stress echocardiography. Heart 2005; 91:737–742. 117. Schuijf JD, Bax JJ, Shaw LJ, et al. Meta-analysis of comparative diagnostic performance of magnetic resonance imaging and multislice computed tomography for noninvasive coronary angiography. Am Heart J 2006; 151:404–411. 118. Cademartiri F, Schuijf JD, Mollet NR, et al. Multislice CT coronary angiography: how to do it and what is the current clinical performance? Eur J Nucl Med Mol Imaging 2005; 32:1337–1347. 119. Dewey M, Teige F, Schnapauff D, et al. Noninvasive detection of coronary artery stenosis with multislice computer tomography or magnetic resonance imaging. Ann Intern Med 2006; 145:407–415. 120. Greenland P. Who is a candidate for noninvasive coronary angiography? Ann Intern Med 2006; 145:466–467. 121. Clark VL, Khaja F. Risk of cardiac catheterization in patients 80 years without previous cardiac surgery. Am J cardiol 1994; 74:1076–1077. 122. West R, Ellis G, Brooks N. Complications of diagnostic cardiac catheterisation: results from a confidential inquiry into cardiac catheter complications. Heart 2006; 92:810–814.

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Angina in the Elderly Wilbert S. Aronow Divisions of Cardiology, Geriatrics, and Pulmonary/Critical Care, Department of Medicine, New York Medical College, Valhalla, New York, U.S.A.

William H. Frishman Department of Medicine, New York Medical College/Westchester Medical Center, Valhalla, New York, U.S.A.

INTRODUCTION Coronary artery disease (CAD) is the number one cause of death in elderly patients and also the major cause of hospitalization and rehospitalizations in this age group. Clinically, CAD manifests as both acute and chronic ischemic syndromes, and it is important that the practicing physician have an understanding of the pathophysiology of these syndromes, as well as confidence in management of these in elderly patients. This chapter will discuss the evaluation and management of elderly patients who demonstrate two of these ischemic syndromes—stable and unstable angina. Recent advances in cellular and molecular biology have provided a better understanding of coronary atherosclerosis, the underlying disease process causing myocardial ischemia. Because of these advances and the development of new therapies, we are now not only able to relieve the patient’s symptoms, but are also able to modify the underlying pathophysiology. Evaluation and treatment of myocardial ischemia in elderly patients pose unique challenges to the physician. Although the pathophysiology of myocardial ischemia and the treatment options are similar in elderly and younger patients, there are significant differences in the presentation and response to treatment between these age groups. Elderly CAD patients with myocardial ischemia often present with “atypical” symptoms, and have more comorbid illnesses, greater number of vessels involved, and worse left ventricular (LV) function (1–6). The pharmacokinetics of medications is altered in elderly patients, and there is often a greater sensitivity to medication and greater potential for side effects and drug-drug interactions. Since elderly patients often present with more advanced CAD and their prognosis is often worse, there is greater potential for gain from aggressive interventions, such as angioplasty [percutaneous transluminal coronary angioplasty (PTCA)] and bypass surgery [coronary artery bypass grafting (CABG)], although the risks are greater compared with younger patients. Finally, elderly patients 269

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and their families may place different values on risk, quality of life, and the importance of prognosis, all of which must be considered by the practicing physician. EVALUATION AND MANAGEMENT The most common symptom of myocardial ischemia in elderly patients as well as in younger patients is exertional chest pain (angina); however, in many older patients, instead of chest pain, exertional dyspnea may be the initial manifestation of ischemia. Other common symptoms experienced by elderly patients with myocardial ischemia are dizziness, mental confusion, or easy fatigability. In some elderly patients with myocardial ischemia, the presentation will be the sudden onset of heart failure (“flash” pulmonary edema) (7–9) or arrhythmias, including sudden death (10). Silent ischemia is particularly common in elderly patients with CAD, occurring in up to one-third of elderly patients, as documented by ambulatory ECG monitoring (11,12). The initial evaluation of the elderly patient with possible myocardial ischemia should begin with a thorough history and complete physical examination, and determination of coronary risk factors and comorbid illnesses. The assessment should determine if the patient is stable or unstable and the risk stratification of the patient. In addition to advanced age, morbidity and mortality in elderly patients with acute myocardial ischemia are directly related to LV function, extent of CAD, and presence of comorbidity. During the evaluation, the physician caring for elderly patients with myocardial ischemia will need to consider the effects of the disease on the whole person (including physical, psychosocial, and economic aspects) and its impact on the patient’s family. Angina pectoris is a clinical syndrome reflecting inadequate oxygen supply for myocardial metabolic demands with resultant ischemia. Depending upon the underlying pathophysiology, the patient will present with stable or unstable angina. The goals of therapy in elderly patients with angina (ischemic syndromes) are to (1) relieve the acute symptoms and stabilize the acute pathophysiological process; (2) minimize the frequency and severity of recurrent anginal attacks; and (3) prevent progression, plus cause regression of the underlying pathophysiological process. Therapeutic measures are directed at modifying the underlying pathophysiology with therapeutic agents and reducing myocardial ischemia by (1) reducing myocardial oxygen demand and (2) increasing coronary blood flow. The main underlying pathological process in patients with angina is coronary atherosclerosis with plaque formation and narrowing of the vessel luminal diameter plus intermittent rupture of the atherosclerotic plaque. Because thrombus formation is an important factor in the progression of atherosclerotic lesions and in the conversion of clinical to acute events after plaque rupture, antiplatelet and anticoagulant therapy is important in the management of elderly CAD patients. In addition, stabilization and regression of the atherosclerotic lesions are possible by vigorous control of the patient’s serum lipids, particularly with hydroxymethylglutaryl coenzyme A (HMG CoA)reductase inhibitors (statins), and treatment of other risk factors such as systemic hypertension, smoking, and diabetes mellitus. The main determinants of myocardial oxygen demand are heart rate, myocardial contractility, and intramyocardial tension, which is a function of systemic pressure and ventricular volume. Reduction of the myocardial oxygen demand includes correction of potentially reversible factors such as heart failure, hyperthyroidism, valvular heart disorders (particularly aortic stenosis), obesity, emotional stress, hypertension, and arrhythmias such as atrial fibrillation. Drug therapy to reduce myocardial oxygen demand

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is directed at reducing myocardial contractility, slowing heart rate, and limiting myocardial tension by reducing systemic pressure (afterload) and preload. Coronary blood flow is dependent upon the duration of cardiac diastole, coronary arterial resistance, aortic diastolic pressure, and the availability of coronary collateral vessels. Improvement in coronary blood flow can be accomplished by these drugs, which increase the duration of diastole, decrease coronary artery resistance by vasodilatation by reducing intramyocardial tension, and stimulate the development of and flow through collateral vessels. SPECIFIC DRUG THERAPIES The principles of drug therapy for treating angina in elderly patients are the same as those for younger patients (13). The physician treating elderly patients, however, must be aware that the pharmacokinetics of drugs may be different in this age group. Gastrointestinal disorders may potentially interfere with drug absorption, although drug bioavailability is usually unaffected by the aging process (14). The decrease in lean body mass and the increase in adipose tissue associated with aging affect the volume of drug distribution. Hepatic blood flow and hepatic oxidation (phase I reactions) decrease with aging, whereas hepatic conjugation is unchanged. Not only is renal dysfunction common in elderly patients, but a 30% decline in glomerular filtration rate between the fifth and ninth decades in normal patients is also associated with aging (14). The elderly often demonstrate increased sensitivity to drugs of any given dosage and may tolerate side effects less well. The presence of comorbid conditions increases the potential for adverse drug reactions. The axiom to remember when prescribing drugs in elderly patients is to start low and titrate up slowly. Given the pharmacological considerations of drug therapy in elderly patients, the specific antianginal drugs can be very effective in controlling symptoms and modifying the underlying pathophysiological process in elderly patients with angina. The classes of drugs commonly used include (1) nitrates, (2) b-blockers, (3) calcium channel blockers, and (4) antiplatelet and/or anticoagulant agents. Nitrates Nitrates are safe, effective, and usually the first choice for treatment of angina. Denitration of the organic nitrate with the subsequent liberation of nitric oxide (NO) is necessary for the drug to have therapeutic effects. NO stimulates guanylyl cyclase, which leads to the conversion of guanosine triphosphate to cyclic guanosine monophosphate, which causes relaxation of vascular smooth muscle with vasodilatation (15,16). The exact mechanism by which the organic nitrates undergo denitration and thus liberate NO remains controversial (17,18). The active metabolite, NO, is also known as the endothelium-derived relaxing factor (EDRF) (19) which, in addition to relaxing vascular smooth muscle, reduces platelet adhesion and aggregation (20). In vessels with atherosclerosis, it has been shown that the endothelium is dysfunctional with attenuation of EDRF activity (21). Such attenuation of EDRF has been found in patients with hypercholesterolemia without overt coronary atherosclerosis (22). Because of this attenuated activity of EDRF, vascular vasoconstriction is predominant in patients with CAD. Therefore, nitrates as exogenous donors of NO would appear to be the ideal drug to use in elderly patients with angina (myocardial ischemia).

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Table 1 Cardiovascular Effects of Nitrates and Mechanisms to Relieve Angina (Ischemia) Decreased myocardial O2 demand Venodilatation ? ; preload ? ; wall tension Arteriolar dilatation ? ; afterload ? ; wall tension Increase myocardial blood flow (O2) Coronary dilatation ? : coronary flow ? : regional myocardial perfusion (subendocardial) Increase collateral flow ? : myocardial perfusion (subendocardial) Decrease coronary resistance ? : coronary flow

The mechanisms by which nitrates relieve and prevent myocardial ischemia include both (1) a reduction in myocardial oxygen demand and (2) an increase in myocardial oxygen supply due to the drug’s potent vasodilator properties (Table 1). Dilatation of capacitance veins reduces ventricular volume and preload, thus lowering myocardial oxygen requirement and improving subendocardial blood flow. Dilatation of systemic conductive arteries decreases afterload, another determinant of oxygen consumption. Nitrates dilate epicardial coronary arteries with an increase in coronary flow and an improvement in subendocardial perfusion. Nitrates also dilate collateral vessels, which can improve blood flow to the areas of ischemia (23). In the doses used clinically, nitrates do not affect coronary resistance vessels (24). Thus, the risk of myocardial ischemia due to coronary steal is minimal, which has been shown to occur with drugs such as dipyridamole and short-acting calcium channel blockers that cause arteriolar dilatation (25). Nitrate Preparations Short-acting nitrates. Nitroglycerin is the drug most frequently used for relief from an acute anginal attack. It is given either as a sublingual tablet or as a sublingual spray and is absorbed rapidly with hemodynamic effects occurring within two minutes of drug administration. The advantage of the spray is that sublingual tablets deteriorate when exposed to light and will need to be renewed every four to six months to ensure complete bioavailability. The other advantage of nitroglycerin spray is that it may be easier to administer in elderly patients who have difficulty with the fine motor skills necessary to administer sublingual tablets. An inhalational form of nitroglycerin has just been approved for the management of acute anginal attacks. Oral nitrates are also available to abort acute anginal attacks that are not relieved with sublingual tablets or spray, and to prevent recurrent anginal attacks. Table 2 lists the different nitrate preparations and dosages (26). Long-acting nitrates. Nitrates have been proven not only effective in relieving acute anginal pain, but also beneficial in preventing recurrent anginal attacks. Long-acting nitrates also improve exercise time until the onset of angina and reduce exercise-induced ischemic ST-segment depression (27,28). The oral preparation is usually the nitrate of choice in the prevention of angina. Standard-formulation isosorbide dinitrate is rapidly absorbed and is typically administered thrice a day with a 14-hour nitrate-free interval. Sustained-release isosorbide dinitrate has a slower rate of absorption and results in a therapeutic plasma concentration for 12 hours. The usual dosage schedule is twice daily in doses of 20 to 80 mg. An isosorbide mononitrate is also available for the prevention of angina. The major advantage of the mononitrate preparation is that it is completely bioavailable because it does not undergo first-pass hepatic metabolism. To avoid drug tolerance, it is recommended

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Table 2 Different Nitrate Preparations and Dosages Medication Short-acting Sublingual nitroglycerin Aerosol nitroglycerin Sublingual and chewable isosorbide dinitrate Intravenous Long-acting Oral isosorbide dinitrate Oral isosorbide dinitrate (SR) Oral erythrityl tetranitrate Oral isosorbide mononitrate Transdermal nitroglycerin

Usual dose (mg)

Onset of action (min)

0.3–0.6 0.4 2.5–10

2–5 2–5 3–15

5 mg/min to 30–80 mg/min 5–40 40 10 5–60 5–15

1

15–30 30–60 30 30 30–60

Duration of action 10–30 min 10–30 min 1–2 hr Sustained during infusion 3–6 hr 6–10 hr Variable 6–8 hr 8–14 hr

Abbreviation: SR, sustained release. Source: From Ref. 26.

that the 20- to 40-mg tablets be given twice daily with a seven-hour interval between doses. Also available is a sustained-release formulation of isosorbide mononitrate that provides therapeutic plasma drug concentrations for up to 12 hours each day and low concentrations during the latter part of the 24-hour period. The drug dose range is 30 to 240 mg given once daily. Transdermal nitroglycerin is a topical nitroglycerin preparation that is effective in preventing angina, and may be particularly beneficial in elderly patients who take numerous pills and have difficulty in remembering drug schedules. Moreover, transdermal nitrate preparations will be more effective than oral preparations in elderly patients who have problems with gastrointestinal malabsorption. Transdermal nitroglycerin is available as an ointment or patch preparation. Both preparations are effective, although the patch obviates some of the inherent messiness of the ointment. As with the oral preparation, a 12- to 14-hour nitrate-free interval is necessary to avoid tolerance when using nitroglycerin ointment or patches. Adverse Effects Elderly patients, in general, tolerate nitrates without significant adverse effects, although the two major side effects, hypotension and headaches, can be extremely bothersome in certain patients. Hypotension may occur within minutes of sublingual administration of a nitrate or one to two hours after oral ingestion and is caused by the reduction in preload and afterload caused by the vasodilator effect of the drug. Symptoms may range from lightheadedness to syncope and are commonly positional and precipitated by standing. The hypotension related to nitrates more commonly occurs following the initial use of the drug, when hypovolemia is present, or with concomitant vasodilator therapy use such as calcium channel blockers or other antihypertensive drugs. The hypotension episode may also be potentiated by alcohol. The episodes can be alleviated by reducing the dose of nitrate, by correcting hypovolemia, and by avoiding an upright position after sublingual use of the drug. In certain elderly patients, the hypotension will be associated with bradycardia, which is similar to a typical vasovagal reaction. The hypotension associated with nitrate use will usually be alleviated by the patients lying down; in certain patients with a severe

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hypotensive reaction, elevation of the legs plus administration of fluid will be necessary. The headache associated with nitrates can be a significant problem in certain elderly patients. It may be a mild, transient frontal headache, although in other patients the headache will be diffuse and throbbing, with persistent head and neck pain associated with nausea or vomiting. Such severe headaches are more common with the use of intravenous or transdermal nitrates. Nitrates may also aggravate vascular headaches and even initiate episodes of “cluster headaches.” As in the management of hypotension related to nitrates, the best approach to alleviate or prevent headaches is to use the lowest doses of nitrates possible and to titrate slowly upward if necessary. The use of an analgesic such as aspirin or acetaminophen in conjunction with the nitrate administration may prevent the associated headache. Commonly, because of vascular adaptation, within 7 to 10 days after initiation of nitrate use, the headache will diminish and subside. However, while waiting for adaptation to occur, elderly patients will require much reassurance to continue using the drug; and in certain elderly patients, a different antianginal drug will have to be substituted for the nitrate because the patient will not be able to tolerate the recurrent headaches. Nitrate tolerance, defined as the loss of hemodynamic and antianginal effects during sustained therapy (29), is another consideration when treating elderly CAD patients. Tolerance has been shown to occur, regardless of the nitrate preparation, if the patient is continuously exposed to nitrates throughout a 24-hour period. The clinical impact of nitrate tolerance, however, is unknown, and the mechanism of nitrate tolerance remains unclear (29,30). Various possible hypotheses include (1) increased intravascular blood volume; (2) depletion of sulfhydryl groups, which are needed for conversion of nitrates to NO; (3) activation of vasoconstriction hormones; and (4) an increased free-radical production by the endothelium during nitrate therapy (31–33). To prevent tolerance, it is recommended that a 12- to 14-hour nitrate-free interval be established when using longacting nitrate preparations. During the nitrate-free interval, the use of another antianginal drug will be necessary. In elderly patients with unstable angina who receive continuous intravenous nitrates, tolerance is not a consideration; if tolerance develops in this setting, the dose of the nitrate should be increased. Studies have demonstrated that abrupt withdrawal of nitrate exposure may produce nonatherosclerotic ischemic cardiac events, including myocardial infarction (MI) (34,35). Such events are presumably due to coronary artery spasm. Therefore, caution should be exercised when high-dose nitrate therapy is discontinued in elderly patients; if possible, the nitrate dose should be slowly tapered downward before discontinuation. Phosphodiesterase inhibitors such as sildenafil, vardenafil, and tadalafil used in the treatment of erectile dysfunction can be safely prescribed to patients with CAD but should not be used in patients receiving long-acting nitrates (36). b-Adrenergic Blockers b-Adrenergic blocking agents are effective in preventing angina and are considered by many authorities to be the drug of choice to prevent ischemic events. b-blockers also improve exercise time until the onset of angina and reduce exercise-induced ischemic STsegment depression (37). b-blockers prevent angina mainly by causing a reduction in myocardial oxygen demand related to slowing of the heart rate, by depressing myocardial contractility, and by reducing blood pressure (Table 3). These effects are particularly impressive in the setting of increased emotional and physical stress, such as during exercise and high anxiety states. In addition to the reduction of myocardial oxygen

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Table 3 Cardiovascular Effects of b-Blockers and Mechanisms to Relieve Angina (Ischemia) Decrease myocardial O2 demand Decrease contractility ? ; blood pressure and ; CO Decrease heart rate ? ; blood pressure and ; CO Increase myocardial blood flow (O2) Decrease heart rate ? : diastolic perfusion time Abbreviation: CO, cardiac output.

Table 4 Pharmacology of b-Blockers and Dosage Generic drug (brand) Propranolol (Inderal) Propranolol LA (Inderal LA) Atenolol (Tenormin) Metoprolol (Lopressor) Metroprolol ER (Toprol XL) Timolol (Blocadren) Carvedilol Acebutolol (Sectral) Pindolol (Visken) Labetalol (Normadyne) Nadolol (Corgard) Esmolol (Brevibloc injection)

Cardioselectivity (relative B1 sensitivity)

ISA

0 0

Lipophilic properties

Usual maintenance dose

0 0

high high

10–40 mg, q.i.d. 40–240 mg, q.d.

þ þ þ

0 0 0

low moderate moderate

25–100 mg, q.d. 25–100 mg, b.i.d. 50–200 mg, q.d.

0 0 þ 0 0 0 þ

0 0 þ þ 0 0 0

low low low moderate low low low

10–20 mg, b.i.d. 25 mg, b.i.d. 200–600 mg, b.i.d. 5–2 mg, t.i.d. 100–600 mg, b.i.d. 40–80 mg, q.d. 0.10–0.15 mg/kg/min

Abbreviations: ER, extended release; LA, long-acting; ISA, intrinsic sympathomimetic activity.

demand, b-blockers increase myocardial oxygen supply by slowing the heart rate and extending the period of diastole. b-Adrenergic blocking agents can be classified according to (1) cardioselectivity, (2) intrinsic sympathomimetic activity, and (3) lipophilic activity (Table 4). Consideration of these specific properties is important when using the drug in elderly CAD patients. Cardioselectivity is determined by the extent the agent is capable of blocking b1 receptors and not b2 receptors (38). Certain agents such as metoprolol and atenolol are relatively more cardioselective than propranolol, which makes these drugs less prone to inducing bronchospasm or peripheral arterial vasoconstriction, as compared with the nonselective agents. At higher doses, however, cardioselective b-blockers react like nonselective agents with full potential for bronchospasm and peripheral arterial constriction. Some b-blockers such as pindolol and acebutolol in addition to blocking b-adrenergic receptors, possess partial agonist properties and, therefore, are capable of producing intrinsic sympathetic stimulation (ISA) (39). The degree to which sympathomimetic activity is clinically apparent depends on the underlying sympathetic activity of the patient receiving the drugs. b-blockers with ISA may prevent slowing of the heart rate, depression of atrioventricular conduction, and a decrease in myocardial contractility in the setting of a low sympathetic state, such as when the patient is resting. When the sympathetic state is high, however, the effect of b-blockers with ISA is similar to that of the usual b-blockers, with a slowing of the heart rate and a decrease in blood pressure and ventricular

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contractility. It should be emphasized that b-blockers with ISA do not prevent sudden death in post-MI patients, as has been demonstrated with the use of the usual b-blockers; therefore, these agents are not recommended in elderly patients who have had an MI (40). The various b-blockers differ with regard to their lipophilic properties. Some b-blockers such as propranolol and metoprolol are highly lipophilic, which facilitates transfer of the drug across the blood-brain barrier and, therefore, the lipophilic agents are more likely to produce central nervous system side effects, including mood changes, depression, and sleeping disturbances (41). In contrast, the hydrophilic b-blockers such as atenolol and nadolol are less likely to produce central nervous system side effects. In general, b-blockers are well tolerated in elderly patients, and some studies have not shown any difference in the prevalence of drug side effects between older and younger patients (42). However, significant drug side effects may occur in elderly patients and may be life threatening. Bradycardia, secondary to the drug effects on the sinus node and atrioventricular conduction, may occur and because of the attenuation of bronchodilatation, asthmatic attacks may be precipitated by the drugs. Therefore, b-blockers are contraindicated in patients with significant bradycardia, unless a pacemaker is inserted, and in persons with a history of bronchospasm. The drugs should also be avoided, or used with caution, in persons with hypotension, hypoglycemic reactions, severe peripheral vascular disease with gangrene, mental depression, and severe heart failure secondary to severe LV systolic dysfunction. The possibility of a withdrawal rebound phenomenon with the activation of acute ischemic events should be considered when discontinuing b-blockers in elderly patients. Accordingly, if possible, the dose of b-blockers should be slowly tapered downward before discontinuation while another antianginal drug should be started; in addition, the patient should be advised to avoid strenuous activities during the tapering period. b-blockers do have effects on serum lipids, which need to be considered when managing elderly CAD patients. Some studies have shown b-blockers to increase triglycerides and to decrease HDL cholesterol, although no significant change was noted in total cholesterol or LDL cholesterol (43). Other studies have not demonstrated a significant effect of long-term propranolol use in serum lipids in elderly persons (44). Patients with angina pectoris should be treated with b-blockers (45,46). Calcium Channel Blockers Calcium channel blockers are usually not considered as first-line drugs in elderly patients with acute coronary artery syndromes. Unlike b-blockers, their effects are less predictable and they have not been shown to reduce mortality, sudden death, or reinfarction in postMI patients. The studies that have shown increase in morbidity and mortality with the use of these drugs in treating hypertension or CAD are also disturbing (47,48). In turn, calcium blockers have cardiovascular effects that can be beneficial in preventing and controlling angina. In general, calcium blockers exert their effect by inhibiting influx of calcium ions through calcium channels of cardiac and vascular smooth muscle cells. Because of this inhibition of calcium influx, myocardial contractility is decreased, dilatation of the peripheral and coronary vasculature occurs, and sinus node and atrioventricular conduction functions are suppressed. Therefore, myocardial oxygen demand is reduced by the decrease in preload and afterload and the decrease in myocardial contractility. Slowing of the heart rate, which occurs with the use of nondihydropyridine calcium blockers such as verapamil and diltiazem is also effective in decreasing myocardial oxygen demand. In addition to reducing the myocardial oxygen demand, calcium blockers can improve the myocardial oxygen supply by relaxing the

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Table 5 Cardiovascular Effects of Calcium Blockers and Mechanisms to Relieve Angina Decreased myocardial O2 demand afterload wall tension Arteriolar vasodilatation Decrease contractility Decrease heart rate Increase myocardial blood flow (O2) diastolic perfusion time Decrease heart rate Coronary vasodilatation ? : flow Table 6 Calcium Channel Blocker Preparations and Dosage

Generic drug (brand) Nifedipine (Procardia) (Adalat) Nifedipine GITS (Procardia XL) Nicardipine (Cardene) Amlodipine (Norvasc) Felodipine (Plendil) Diltiazem (Cardizem) Diltiazem CD (Cardizem CD) Verapamil (Isoptin) (Calan) (Verelan) Verapamil SR (Isoptin SR) (Calan SR)

Potential for SA node and AV node depression

Potential for depression of myocardial contractility

0

0 to þ

10–30, t.i.d.

0

0 to þ

30–90, q.d.

0 0 0 þþ þþ þþ

0 to þ 0 0 þ þ þþ

20–30, t.i.d. 2.5–10, q.d. 2.5–20, q.d. 30–90, t.i.d. 120–300, q.d. 40–120, t.i.d.

þþ

þþ

120–240, q.d.

Usual adult oral dosage (mg)

Abbreviations: CD, extended release; GITS, gastrointestinal therapeutic system; SR, sustained release. Source: From Ref. 26.

tone of coronary arteries and by promoting the development of coronary collaterals (Table 5). This property of relaxing coronary vasculature tone is particularly beneficial when Prinzmetal’s angina (vasospasm) is present. Calcium channel blockers are usually divided into the dihydropyridine and nondihydropyridine groups (Table 6). Nifedipine was the first dihydropyridine made available for the treatment of angina, but newer generations of dihydropyridine agents are now available, including nicardipine, nisoldipine, nimodipine, felodipine, amlodipine, and isradipine. Nifedipine is a potent coronary and peripheral artery vasodilator with negative inotropic properties. Significant afterload reduction occurs due to the vasodilation. At therapeutic doses, nifedipine has only a minor effect on the sinus and atrioventricular nodes; thus because of the decrease in afterload, sympathetic reflex increases in heart rate commonly occur when the drug is administered. The increased heart rate may ameliorate the negative inotropic effect, and clinically hemodynamic indices of contractility are generally unaffected. Because of intense vasodilation of the peripheral coronary circulation, however, the possibility of a coronary steal phenomenon has to be considered when using the drug (49). Such a phenomenon is more common when using a short-acting drug preparation and in patients with severe three-vessel CAD. Therefore, a b-blocker should be added if nifedipine is used to treat elderly patients with acute ischemic syndromes. A sustained-release preparation of nifedipine is now available, which results in less sympathetic activity and is

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considered to be a safer agent than the shorter-acting preparations. Nevertheless, the addition of a b-blocker with nifedipine, regardless of the type of preparation, is considered the best approach when managing elderly patients with acute ischemic syndromes. The second-generation dihydropyridines such as amlodipine and felodipine have greater vascular selectivity and less negative inotropy and have no clinical effect on the sinus or atrioventricular nodes. Therefore, coronary artery steal does not appear to be a major concern with these drugs, and the drugs can be used in elderly patients with LV systolic dysfunction. Verapamil and diltiazem, two non-dihydropyridine agents, are both potent inhibitors of sinus node activity and atrioventricular node conduction, in addition to being peripheral vasodilators (Table 6). Both drugs have significant negative inotropic effects. Because of these effects, the drugs are effective antianginal agents; however, caution is necessary when using the drugs in elderly patients with bradycardia and depressed LV systolic function. These drugs are contraindicated in patients with LV systolic dysfunction with or without clinical heart failure, in patients with disorders of the sinus node, and in patients with heart block. The Multicenter Diltiazem Postinfarction Trial reported an increased mortality in postinfarction patients with heart failure or abnormal LV ejection fraction who were randomized to diltiazem therapy (50). Therefore, if a calcium channel blocker is necessary to control angina in elderly postinfarction patients with depressed LV systolic function, second-generation dihydropyridines such as amlodipine and felodipine should be used instead of diltiazem or verapamil. Extreme caution is required when using diltiazem or verapamil in combination with a b-blocker, particularly in elderly patients who demonstrate sinus node or atrioventricular conduction dysfunction, or in elderly patients who have depressed LV systolic function. Some authorities recommend ECG monitoring when initiating these drugs, particularly verapamil, in combination with b-blockers. It should be emphasized that the American College of Cardiology/American Heart Association (ACC/AHA) guidelines state that there are no Class I indications for using calcium channel blockers during or after MI (51). However, if angina pectoris persists despite the use of b-blockers and nitrates, long-acting calcium channel blockers such as dilatiazem or verapamil should be used as antianginal agents in elderly patients with CAD and normal LV systolic function and amlodipine or felodipine in patients with CAD and abnormal LV systolic function.

Aspirin Recent knowledge of the importance of thrombus formation in acute coronary syndromes and the results of studies demonstrate a decreased incidence of MI in patients taking daily aspirin compared with patients receiving placebo (52). The updated ACC/AHA guidelines for the management of patients with stable angina pectoris (45) and the American College of Physicians clinical practice guidelines (46) recommend treating all patients with CAD with aspirin in a dose of 75 to 325 mg daily unless there are contraindications to the use of this drug. The use of enteric low dose aspirin may be associated with aspirin resistance (a lack of an antiplatelet effect) and a 160-mg aspirin dose may need to be prescribed. In an observational prospective study of 1410 patients, mean age 81 years, with prior MI and hypercholesterolemia, 59% of patients were treated with aspirin (50) and at 36-month follow-up, the use of aspirin was associated with a 52% reduction in new coronary events (53).

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Ticlopidine and Clopidogrel Not all patients can tolerate aspirin, and recently an aspirin-resistance phenomenon has been described in patients where there is little-to-no antiplatelet effect from the drug. Ticlopidine and clopidogrel are useful alternatives to aspirin when the drug is not tolerated, although these have their own associated toxicities (54). This toxicity may, however, be dose related in most situations. Clopidogrel in a dose of 75 mg daily is recommended in patients who cannot tolerate aspirin (45,46,52,55). Dipyridamole should not be used in patients with angina pectoris since it can cause a coronary steal syndrome and increase exercise-induced myocardial ischemia (56). Other Adjunctive Treatments Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers On the basis of the results of various clinical trials, there is now strong evidence that angiotensin-converting enzyme (ACE) inhibitors can reduce the frequency of new cardiovascular events in both normotensive and hypertensive patients with known vascular disease and in patients with diabetes mellitus. If tolerated, ACE inhibitors should be part of a medical regimen to treat chronic ischemic heart disease (57). Angiotensin I receptor blockers are now being studied in patients with known ischemic heart disease who have no history of a previous MI or LV dysfunction. Statins Numerous studies have demonstrated that statins reduce cardiovascular morbidity and mortality in elderly patients with CAD including those with stable angina pectoris (58–65). The low-density lipoprotein cholesterol should be reduced to less than 70 mg/dL in patients with stable angina pectoris (63,64). The updated ACC/AHA guidelines for management of patients with chronic stable angina pectoris (45) and the ACP clinical practice guidelines (46) both recommend treating patients with chronic stable angina pectoris with lipid-lowering drug therapy. AN APPROACH TO MANAGEMENT: SPECIFIC PRACTICE CONSIDERATIONS Unstable Angina Unstable angina is a transitory syndrome that results from disruption of a coronary atherosclerotic plaque with the subsequent cascade of pathological processes, including thrombosis formation that critically decreases coronary blood flow resulting in new onset or exacerbation of angina (ischemia) (66). Transient episodes of vessel occlusion or near occlusion by thrombus at the site of plaque injury may occur and lead to angina at rest. The thrombus may be labile and result in temporary obstruction to flow. Release of vasoconstrictive substances by platelets and vasoconstriction secondary to endothelial vasodilator dysfunction can contribute to further reduction in blood flow (67), and in some patients myocardial necrosis (non-Q-wave infarction) is documented. Table 7 lists the various clinical presentations that are classified as unstable angina. In contrast to elderly patients with stable angina who do not require hospitalization, elderly patients with unstable angina are usually hospitalized and, depending upon their risk stratification, may require monitoring in an intensive care unit. Severe classification

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Table 7 Unstable Angina Presentations Rest angina within one week of presentation New-onset angina of CCSC class III or IV within two months of presentation Angina increasing in CCSC class to at least CCSC III or IV Variant angina Non-Q-wave myocardial infarction Postmyocardial infarction angina (>24 hr) Abbreviation: CCSC, Canadian Cardiovascular Society Classification.

Table 8 Risk Stratification Scheme of Unstable Angina Based on Presenting Clinical Characteristics Risk classa

Clinical characteristics

IA IB II

Acceleration of previous exertional angina without ECG changes Acceleration of previous exertional angina with ECG changes New onset of exertional angina

III IV

New onset of rest angina Coronary insufficiency syndrome; protracted chest pain >20 min with persistent ECG changes

a

IA, lowest risk for in-hospital complications; IV, highest risk for in-hospital complications. Abbreviation: ECG, electrocardiogram. Source: From Ref. 68.

schemes of risk stratification have been developed. Table 8 lists a classification that subdivides patients into high-, intermediate-, and low-risk groups (68). As noted by this classification, clinical characteristics are readily identifiable on the initial patient evaluation that stratifies the patient into low-, intermediate-, or high-risk subgroups for hospital complications. For example, acute resting ischemic ECG abnormalities markedly worsen the prognosis. Other characteristics that identify the high-risk patient include prolonged ongoing rest pain longer than 20 minutes and signs of LV dysfunction (S3, rales, new murmur or mitral regurgitation). Within each subgroup of unstable angina, it is important to recognize certain elderly patients who have specific characteristics that will influence therapy. Recurrent angina after PTCA is a common clinical event related to partial artery restenosis and occurs in as many as 40% of patients within the first three to six months post-PTCA, regardless of the patient’s age. The prognosis is favorable, and the elderly patient can usually be stabilized medically prior to a scheduled repeat angiogram and a possible repeat PTCA. Angina after intracoronary stent placement occurs less frequently than after an isolated angioplasty and is often the result of subacute closure due to thrombus formation. These patients are at higher risk for MI and are usually managed as higher-risk patients (69). Patients with angina following CABG are another subgroup of elderly patients who require specific considerations. Since the risk of reoperation is higher than that of the initial surgery, surgeons are often reluctant to reoperate in elderly patients, especially on those elderly patients who have undergone internal mammary grafting. Medical therapy is usually the first approach to this subgroup of elderly patients with unstable angina. Other clinical subgroups of elderly patients with unstable angina who require special considerations are the patient with a non-Q-wave infarction, variant angina, and cocaine intoxication. Table 9 lists the ACC/AHA stratification of patients with unstable angina into highrisk, intermediate-risk, and low-risk groups for short-term risk of death or nonfatal MI

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Table 9 Risk Stratification of Patients With Unstable Angina for Short-Term Risk of Death or Nonfatal MI High Risk (at least one of following factors) Accelerating tempo of ischemic symptoms in prior 48 hr Prolonged ongoing (>20 min) rest pain

Pulmonary edema; new or worsening MR murmur; S3 or new/worsening rales; hypotension, tachycardia, bradycardia; age >75 yr Angina at rest with transient ST-segment changes >0.05 mV; bundle branch block, new or presumed new; sustained ventricular tachycardia Markedly elevated troponin T or I (>0.1 ng/mL)

Intermediate risk (no highrisk feature but one of the following features) Prior MI or CABG; peripheral or cerebrovascular disease; prior aspirin use Prolonged (>20 min) rest angina, now resolved, with moderate or high likelihood of CAD; rest angina (<20 min or relieved with rest or sublingual NTG) Age >70 yr

Low risk (no high- or intermediate-risk feature) —

New-onset CCS Class III or IV angina in past 2 wk with moderate or high likelihood of CAD

—

T-wave inversions >0.2 mV; pathological Q-waves

Normal or unchanged ECG during episode of chest discomfort

Slightly elevated troponin T or I (>0.01 but <0.1 ng/mL)

Normal

Abbreviations: MI, myocardial infarction; CABG, coronary artery bypass graft surgery; CAD, coronary artery disease; CCS, Canadian Cardiovascular Society; NTG, nitroglycerin; MR, mitral regurgitation. Source: Adapted from Ref. 70.

(70). Following risk stratification of the elderly patient with unstable angina, therapy should be initiated. The initial goals of therapy should be to alleviate symptoms by decreasing myocardial oxygen demand and increasing myocardial blood flow and to stabilize the atherosclerotic plaque. Furthermore, a plan to promote regression of the atherosclerotic lesion should be initiated during the patient’s hospitalization. Therapy, including drug therapy, should be started in the emergency department; it should not be delayed until hospital admission. Reversible factors causing angina should be identified and corrected. These include anemia, which may require packed red cell transfusion. Electrocardiographic monitoring is important since arrhythmias can occur and ST-T changes are a marker for an increased risk of complications. The aggressiveness of the drug dosage will depend upon the severity of symptoms and will need modification through the elderly patient’s hospitalization. Oxygen should be given to patients with cyanosis, respiratory distress, heart failure, or high-risk factors. Oxygen therapy should be guided by arterial saturation; its use when the baseline saturation is more than 94% is questionable. Morphine sulfate should be administered intravenously when symptoms are not immediately relieved with nitroglycerin or when acute pulmonary congestion and/or severe agitation is present. Aspirin should be given to all patients with unstable angina unless contraindicated and continued indefinitely. Clopidogrel should be administered to patients who are unable

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to tolerate aspirin because of hypersensitivity or major gastrointestinal intolerance. Data from the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial favor the use of aspirin plus Clopidogrel for nine months in patients with unstable angina (71). The ACC/AHA guidelines for unstable angina support the use of aspirin plus clopidogrel in high-risk and intermediate-risk patients with unstable angina, with clopidogrel withheld for five to seven days if CABG is planned (72). Parenteral anticoagulation with intravenous infractionated heparin or preferably with subcutaneous low-molecular-weight heparin (73–76) should be added to antiplatelet therapy in patients with high-risk or intermediate-risk unstable angina. The revised ACC/AHA guidelines for unstable angina also recommend adding a platelet glycoprotein IIb/IIIa inhibitor in addition to aspirin, clopidogrel, and low-molecular–weight heparin in patients with continuing ischemia or with other high-risk features, and to patients in whom PTCA is planned. Eptifibatide and tirofiban are approved for this use (70). Abciximab can also be used for 12 to 24 hours in patients with unstable angina in whom PTCA is planned within the next 24 hours (70). As with the use of aspirin, nitrates should be instituted quickly in the emergency department. Patients whose symptoms are not fully relieved with three sublingual nitroglycerin tablets should receive continuous intravenous nitroglycerin. The initial dose is 5 to 10 mg/min, and the dose should be titrated every three to five minutes to relieve symptoms of associated hypertension. If angina is relieved, then an oral or transdermal preparation can be started after 24 hours of intravenous therapy. b-blockers (in addition to aspirin, heparin, and nitrates) should also be started in the emergency room unless there are contraindications. Intravenous loading (e.g., metoprolol 5 mg for 5 minutes, repeated every 15 minutes for a total of 15 mg) or propranolol followed by oral therapy is recommended. A continuous b-blocker intravenous infusion may be used (esmolol, starting maintenance dose of 0.1 g/kg/min intravenously with upward titration in increments of 0.5 g/kg/min every 10 to 15 minutes as tolerated by blood pressure until the desired response has been obtained, limiting symptoms develop, or a dose of 0.20 mg/min is reached). An oral ACE inhibitor and a statins drug should also be administered unless there are contraindications. Interventional Therapy The majority of elderly patients with stable and unstable angina can be stabilized with medical management. Patients who continue to have unstable angina 30 minutes after initiation of therapy or who have recurrent unstable angina during the hospitalization are at increased risk for MI or cardiac death. In addition, patients who demonstrate major ischemic complications, such as pulmonary edema, ventricular arrhythmias, or cardiogenic shock associated with unstable angina also have a poor prognosis. In these patients, emergency cardiac catheterization should be performed with the consideration of interventional therapy (CABG or PTCA). Insertion of an intra-aortic balloon pump may be necessary in some of these elderly patients. For the majority of elderly patients whose angina is stabilized, two alternate strategies for definitive treatment of angina need to be considered: “early invasive” and “early conservative” (77). The “early invasive strategy” approach is to perform cardiac catheterization in all patients after 48 hours of presentation unless interventional therapy is contraindicated because of extensive comorbidities. In contrast, the “early conservative” strategy is to perform cardiac catheterization only in patients who have one or more of the following high-risk indicators: prior revascularization, associated congestive heart failure or depressed LV ejection fraction (<50%) by noninvasive study, malignant

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ventricular arrhythmia, persistent or recurrent pain/ischemia, and/or a functional study (stress test) indicating high risk. On the basis of data from the Treat Angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy (TACTICS)—Thrombolysis in Myocardial Infarction 18 study, an early invasive strategy is superior to a conservative strategy in high-risk unstable angina patients (78). The revised ACC/AHA guidelines recommend an early invasive strategy for all high-risk patients with unstable angina. A stress test can be performed 48 to 72 hours after the patient has stabilized. The choice of the type of stress testing (exercise, exercise with imaging, or pharmacological) will depend upon the resting ECG findings and the patient’s ability to exercise. Myocardial revascularization is indicated in (1) patients who, at catheterization, are found to have significant left main CAD (50%) or a significant (70%) three-vessel disease with depressed LV function (LV ejection fraction <50%); (2) patients with twovessel disease with proximal severe subtotal stenosis (95%) of the left anterior descending coronary artery and depressed LV ejection fraction; and (3) patients with significant CAD if they fail to stabilize with medical treatment, have recurrent angina/ ischemia at rest or with low-level activities, and/or if ischemia is accompanied by congestive heart failure symptoms, an S3 gallop, new or worsening mitral regurgitation, or definite ECG changes (77). The ACC/AHA guidelines recommend CABG for patients with unstable angina with significant left main CAD, three-vessel CAD, and for two-vessel CAD with significant proximal left anterior descending CAD and either abnormal LV function (LV ejection fraction <50%) or demonstrable ischemia on noninvasive testing (70). PTCA or CABG is recommended for patients with one-vessel or two-vessel CAD without significant proximal left anterior descending CAD, but with a large area of viable myocardium and high-risk criteria on noninvasive testing. PTCA is recommended for patients with multivessel CAD with a suitable coronary anatomy with normal LV function and without diabetes mellitus (70). For some patients without these high-risk features, revascularization may still be an option, depending on recurrent symptoms, test results, and patient preferences. The healthcare team should educate patients and their families or advocate about the expected risks and benefits of revascularization and determine individual patient preferences and fears that may affect the selection of therapy. CABG, with or without cardiopulmonary bypass, causes a high incidence of cognitive decline (79). Interventional therapy with PTCA, atherectomy, and/or some combination of PTCA and coronary artery stenting has increased in usage in patients with CAD, diminishing the frequency of CABG. Studies comparing PTCA and CABG have been performed, and, generally, the results of PTCA and CABG are similar in reference to mortality. However, an increased incidence of recurrent angina and need for revascularization procedure occurs with PTCA (80–82). On the other hand, the incidence of cognitive decline is high in older persons undergoing CABG with no difference seen when comparing the incidence of cognitive dysfunction in on-pump and off-pump bypass procedures (79). Further studies are necessary to determine if coronary stenting in conjunction with PTCA will decrease the incidence of recurrent angina and the need for revascularization. Stable Angina Elderly patients with stable angina who are at “low risk” (preserved LV function and no left main CAD) can be treated as effectively with medical therapy as with interventional therapy. In patients with stable angina, the atherosclerotic lesions are predominantly

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advanced fibrolipoid plaques or fibrotic lesions (83). Usually no plaque ulceration or thrombosis is present, and the main cause of angina is the reduction of luminal diameter of the coronary vessel due to chronic atherosclerosis. Therefore, therapy is directed at decreasing myocardial oxygen demand and increasing coronary blood flow. In addition, prevention of plaque instability and initiation of therapy to cause regression of the atherosclerotic lesion are necessary. Studies have not demonstrated any significant benefit of a specific class of antianginal drugs compared with other classes in treatment of stable angina. Therefore, the choice of a single antianginal drug will depend upon the clinical situation, contraindications, and the physician’s preference. Surely, a b-blocker should be the first choice in elderly patients who have a history of MI or demonstrate electrocardiographic evidence of silent infarction or silent myocardial ischemia (84). Combination drug therapy, in which a b-blocker and a vasodilator are used, is highly advantageous in treating elderly patients with angina. Studies have shown that combination therapy with a nitrate and a b-blocker decreases the number of anginal attacks and increases the duration of treadmill stress testing as compared with either nitrates or b-blockers alone (85). The combination of a b-blocker and a calcium channel blocker has also been shown to be more effective in reducing angina and extending exercise time than monotherapy (85). Such a combination can be very beneficial when attempting to control both hypertension and angina in elderly patients. In turn, caution is necessary when using b-blockers in combination with diltiazem or verapamil because of the potential risk of provoking serious bradycardia or precipitating heart failure. This therapy is particularly a concern when verapamil and a b-blocker are used in combination, and when underlying sinus or atrioventricular nodal disease or LV systolic dysfunction is present. In elderly patients whose angina is refractory to double drug therapy, triple drug therapy may be necessary. Such a therapy would include a b-blocker, a long-acting nitrate, and a calcium channel blocker. It may be beneficial in preventing anginal attacks. However, elderly patients taking these multiple drugs will need to be monitored closely for side effects, and the drugs should be started at low doses. Patients aged 75 years or older with angina, despite standard drug therapy, benefit more from coronary revascularization (86,87). A preventive program in elderly patients with angina is mandatory, including abstinence from smoking, treatment of hypertension, use of aspirin and ACE inhibitors, an exercise program, and control of lipids and weight. Treatment of associated heart failure and anemia can also prevent or relieve symptoms of angina. The recent studies that have demonstrated the efficacy of statin therapy in lowering serum lipids and in preventing future coronary events in elderly patients with CAD (58–65) compel physicians to screen elderly anginal patients for elevated serum lipids and to be aggressive in their treatment of lipid abnormalities. In the Heart Protection Study, 20,536 adults up to age 80 years with CAD, other occlusive arterial disease, or diabetes mellitus were randomized to simvastatin 40 mg daily or double-blind placebo and followed for a mean of five years (62). All-cause mortality, coronary events, stroke, and coronary and noncoronary revascularization were significantly reduced by simvastatin, regardless of age and initial serum lipids (62). In addition, elderly patients will require counseling in reference to lifestyle, with avoidance of activities that “trigger” ischemic attacks (88). The physician will need to be aware of the potential for the development of mental depression in elderly CAD patients. The symptoms of depression may be subtle in elderly patients and will progress unless the disease is treated. Depression has also been shown to be a risk factor for future coronary events in patients with CAD (89).

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The role of exercise should be emphasized when managing elderly patients with angina. Exercise programs that progressively increase physical endurance and reduce the heart rate and cardiac work at any given level of activity lead to improvement in cardiac performance and prolong exercise time before onset of angina (90). In addition, some studies have shown stress-induced myocardial ischemia (as assessed by thallium 201 scintigraphy) to be significantly decreased after a one-year program of supervised exercise and low-cholesterol diet in patients with stable angina (91). Caution is necessary, however, when initiating an exercise program in elderly CAD patients. Elderly patients should be screened for high-risk characteristics, including results of a stress test, before starting an exercise program since exercise can provoke serious arrhythmias in high-risk patients, especially in poorly conditioned patients. Other exercise programs can be advised according to the patient’s needs and preference, such as swimming or stationary cycling. New Approaches for the Management of Angina Over the years, the management of patients with angina has changed, and new approaches have developed. Some of these changes are due to increased knowledge of the underlying pathophysiology of myocardial ischemia with the development of new drugs. Other changes are related to the development of innovative mechanical devices and techniques that theoretically should relieve angina. Ranolazine Ranolazine is a piperazine derivative and a partial fatty acid oxidation inhibitor that reduces calcium overload in the ischemic myocyte by inhibition of the late sodium current (92,93). This action decreases the magnitude of ischemia-induced sodium and calcium overload, improving myocardial function as well as myocardial perfusion. Four randomized, doubleblind trials have demonstrated that ranolazine reduces frequency of angina episodes and nitroglycerin consumption and improves exercise duration and time to anginal attacks without clinically significant effects on heart rate or blood pressure (94–97). Ranolazine was approved by the US Food and Drug Administration (FDA) for treatment of patients with chronic stable angina pectoris in January 2006. Ranolazine was approved for use as a combination therapy when angina is not adequately controlled with other antianginal drugs. The recommended dose of sustained-release ranolazine is 750 mg or 1000 mg twice daily. Other Pharmacological Approaches Other drugs under investigation and being considered for FDA approval include nicorandil and ivabradine. Nicorandil is a coronary vasodilator with a unique dual mechanism of action that involves a nitrate-like effect and a potassium ion channel opening action (92,98). The Impact of Nicorandil in Angina (IONA) study showed at 1.6-year follow-up in patients with stable angina pectoris that 2565 patients randomized to nicorandil 20 mg twice daily had a 17% significant reduction in CAD death, nonfatal MI, or unplanned hospital admission for cardiac chest pain compared with 2561 patients randomized to placebo (99). Ivabradine is a heart rate lowering drug that acts specifically on the sinoatrial node (100). Ivabradine caused dose-dependent improvements in exercise tolerance and time to development of ischemia during exercise (101).

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Cell Therapy Innovative approaches for the management of drug resistant angina pectoris include the use of vascular growth factors to induce myocardial angiogenesis (102,103). Granulocyte macrophage colony stimulating factor has been used to mobilize bone marrow stem cells to induce angiogenesis. In addition, stem cells are being used by direct injection to affect new vascular growth (103). Other Mechanical Approaches Recent mechanical techniques for the treatment of angina include transmyocardial laser revascularization (TMLR), enhanced external counter pulsation (EECP), and spinal cord stimulation (SCS). These approaches have been used in patients with severe angina who are not candidates for PTCA or CABG, usually because of diffuse CAD or extreme comorbidities. Such approaches would appear to be suitable for many elderly CAD patients who may have inoperable CAD and multiple comorbidities plus angina that is difficult to control with medical therapy. TMLR employs a high-energy laser beam to create channels in the myocardium from the epicardial to the endocardial surface (104). The channels allow oxygenated LV blood to perfuse ischemic myocardial zones (105). The human myocardium contains an extensive network of sinusoids, and TMLR, theoretically, delivers oxygenated blood to these sinusoids with improved myocardial oxygen delivery to the ischemic region. Data on the efficacy of TMLR in improving anginal symptoms and exercise capacity are controversial (106–108). EECP is a noninvasive outpatient treatment designed to increase coronary flow in the treatment of angina (109). This treatment involves wrapping the calves, thighs, and buttocks with pneumatic cuffs. Synchronized pulsatory pressure is applied sequentially from calves to thighs during diastole, returning arterial blood to the heart to increase diastolic pressure in the coronary vessels. Pressure is relieved during systole, reducing afterload and cardiac work, thus decreasing myocardial oxygen demand. The typical course of treatment is 35 one-hour sessions over a period of seven weeks. EECP has been shown to improve ischemia in patients who have thallium reperfusion evidence of ischemia. In one study of patients who received EECP, 75% of subjects had resolution of ischemia, demonstrated by improved thallium scintigraphy with normal thallium stress tests, except for areas scarred by previous MIs (110). In addition, the subjects showed exercise improvement. A controlled study of 139 patients showed a reduction in anginal episodes, an increase in the time to 1-mm ischemic ST-segment depression, and a trend toward reduced nitroglycerin use in the EECP group but a similar increase in exercise duration in both groups (111). SCS has been demonstrated to cause clinical improvement in patients with refractory angina pectoris in the number of anginal episodes, in nitroglycerin consumption, in maximal exercise time, in exercise time until angina, in the number of episodes of myocardial ischemia, in the duration of episodes of myocardial ischemia, and in ischemic ST-segment depression at a comparable workload (112,113). Double-blind, randomized, placebo-controlled studies have not been performed with SCS. The clinical improvement from SCS occurred despite no evidence of improvement in regional myocardial blood flow during exercise or in myocardial oxygen consumption as assessed by the heart rate times systolic pressure product at maximal exercise. The mechanisms of clinical improvement by SCS are unclear. SCS must be considered experimental at this time and is a therapeutic option for the treatment of refractory angina pectoris in patients unable to have coronary revascularization or at very high risk for coronary revascularization.

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83. Gallo R, Badimon JJ, Fuster V. Pathobiology of coronary ischemic events: clinical implications. Adv Intern Med 1998; 43:203–232. 84. Aronow WS, Ahn C, Mercando AD, et al. Decrease in mortality by propranolol in patients with heart disease and complex ventricular arrhythmias is more an anti-ischemic than an antiarrhythmic effect. Am J Cardiol 1994; 74:613–615. 85. Aronow WS. Medical management of stable angina pectoris. Comp Ther 1987; 13(4):54–60. 86. The TIME Investigators . Trial of invasive versus medical therapy in elderly patients with chronic symptomatic coronary-artery disease (TIME): a randomised trial. Lancet 2001; 358:951–957. 87. Aronow WS. Commentary. Approach to symptomatic coronary disease in the elderly: TIME to change? Lancet 2001; 358:945–946. 88. Willich SN, Lewis M, Lowel H, et al. Physical exertion as a trigger of acute myocardial infarction. N Engl J Med 1993; 329:1684–1690. 89. Frasure-Smith N, Lesperance F, Talajic M. Depression following myocardial infarction. Impact on six-month survival. JAMA 1993; 270:1819–1825. 90. Aronow WS. Exercise therapy for older persons with cardiovascular disease. Am J Geriatr Cardiol 2001; 10:245–252. 91. Schuler G, Schlierf G, Wirth A, et al. Low-fat diet and regular supervised physical exercise in patients with symptomatic coronary artery disease: reduction of stress-induced myocardial ischemia. Circulation 1988; 77:172–181. 92. Frishman WH, Retter A, Mikailidis J, et al. Innovative pharmacologic approaches to the treatment of myocardial ischemia. In: Frishman WH, Sonnenblick EH, Sica D, eds. Cardiovascular Pharmacotherapeutics. 2nd ed. New York: McGraw-Hill, 2003. 93. Belardinelli L, Antzelevitch C, Fraser H. Inhibition of late (sustained/persistent) sodium current: a potential drug target to reduce intracellular sodium dependent calcium overload and its detrimental effects on cardiomyocyte function. Eur Heart J 1994; 9(suppl 1):13–17. 94. Chaitman BR, Skettino SL, Parker JO, et al. Anti-ischemic effects and long-term survival during ranolazine monotherapy in patients with chronic severe angina. J Am Coll Cardiol 2004; 43:1375–1382. 95. Chaitman BR, Pepine CJ, Parker JO, et al. Effects of ranolazine with atenolol, amlodipine, or diltiazem on exercise tolerance and angina frequency in patients with severe chronic angina: a randomized controlled trial. JAMA 2004; 291:309–316. 96. Rousseau MF, Pouleur H, Cocco G, et al. Comparative efficacy of ranolazine for chronic angina pectoris. Am J Cardiol 2005; 95:311–316. 97. Stone PH, Gratsiansky NA, Blokhin A, et al. Antianginal efficacy of ranolazine when added to treatment with amlodipine: the ERICA (Efficacy of Ranolazine in Chronic Angina) trial. J Am Coll Cardiol 2006; 48:566–575. 98. Taira N. Nicorandil as a hybrid between nitrates and potassium channel activators. Am J Cardiol 1989; 63:18J–24J. 99. The IONA Study Group . Effect of nicorandil on coronary events in patients with stable angina: the Impact of Nicorandil in Angina (IONA) randomised trial. Lancet 2002; 359:1269–1275. 100. DiFrancesco CD, Camm JA. Heart rate lowering by specific and selective If current inhibition with ivabradine. A new therapeutic perspective in cardiovascular disease. Drugs 2004; 64:1757–1765. 101. Borer JS, Fox K, Jaillon P, et al. Antianginal and antiischemic effects of ivabradine, an If inhibitor, in stable angina. A randomized, double-blind, multicentered, placebo-controlled trial. Circulation 2003; 107:817–823. 102. Takano H, Komuro I. Cytokines and heart remodeling. In: Leri A, Anversa P, Frishman WH, eds. Cardiovascular Regeneration and Stem Cell Therapy. Malden, MA: Blackwell Futura, 2007:139–147. 103. Deedwania PC, Chatterjere K. Current therapeutic options and evolving therapies for chronic stable angina/chronic coronary syndrome. Johns Hopkins Adv Stud Med 2006; 6(9A):S827–S836.

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104. Frazier OH, Cooley DA, Kadipasaoglu KA, et al. Myocardial revascularization with laser. Preliminary findings. Circulation 1995; 92(9 suppl):II58–II65. 105. Donovan CL, Landolfo KP, Lowe JE, et al. Improvement in inducible ischemia during dobutamine stress echocardiography after transmyocardial laser revascularization in patients with refractory angina pectoris. J Am Coll Cardiol 1997; 30:607–612. 106. Lauer B, Junghans U, Stahl F, et al. Catheter-based percutaneous myocardial laser revascularization in patients with end-stage coronary artery disease. J Am Coll Cardiol 1999; 34:1663–1670. 107. Schofield PM, Sharpies LD, Caine N, et al. Transmyocardial laser revascularization in patients with refractory angina: a randomised controlled trial. Lancet 1999; 353:519–524. 108. Oesterle SN, Sanborn TA, Ali N, et al. Percutaneous transmyocardial laser revascularisation for severe angina: the PACIFIC randomised trial. Lancet 2000; 356:1705–1710. 109. Soroff HS, Hui J, Giron F. Current status of external counterpulsation. Crit Care Clin 1986; 2:277–295. 110. Lawson WE, Hui JCK, Soroff HS, et al. Efficacy of enhanced external counterpulsation in the treatment of angina pectoris. Am J Cardiol 1992; 70:859–862. 111. Arora R, Chou T, Jain D, et al. External Counter Pulsation (MUST-EECP): effect of EECP on exercise-induced myocardial ischemia and anginal episodes. J Am Coll Cardiol 1999; 33:1833–1840. 112. Aronow WS, Frishman WH. Spinal cord stimulation for the treatment of angina pectoris. Curr Treat Options Cardiovasc Med 2004; 6:79–83. 113. Aronow WS, Frishman WH. Spinal cord stimulation for the treatment of angina pectoris. In: Frishman WH, Weintraub WI, Micozzi MS, eds. Complementary and Integrative Therapies for Cardiovascular Disease. Philadelphia: Elsevier, 2005:390–395.

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Therapy of Acute Myocardial Infarction Michael W. Rich Washington University School of Medicine, St. Louis, Missouri, U.S.A.

INTRODUCTION In 2004, there were 732,000 hospital admissions in the United States with a first-listed diagnosis of acute myocardial infarction (MI) (1). Of these, 460,000 (62.8%) occurred in the 12.4% of the population aged 65 years or older, 42.3% occurred in the 6.1% of the population over the age of 75, and 17.1% occurred in the 1.6% of the population over the age of 85 (1). Moreover, approximately 85% of all deaths attributable to acute MI occur in patients over age 65, and 60% occur in patients over age 75 (1,2). Thus, acute MI is exceedingly common in older adults, and the case fatality rate is disproportionately high. This chapter reviews the treatment of elderly patients with acute MI, including the management of selected complications. GUIDING PRINCIPLES Numerous studies have demonstrated that elderly patients with acute MI are at increased risk for a variety of complications, including atrial fibrillation, congestive heart failure, myocardial rupture, cardiogenic shock, and death (3–9). The risk of each of these complications is two- to fourfold higher in patients over age 65 than in younger patients. Older age thus defines a high-risk subgroup of MI patients who could potentially derive substantial benefit from aggressive therapeutic interventions. On the other hand, elderly patients are at increased risk for serious adverse consequences arising from aggressive treatments such as fibrinolytic therapy or early catheterization and percutaneous coronary intervention (PCI). In addition, the risk–benefit ratio may be modulated by the presence of comorbid conditions (e.g., diabetes, renal insufficiency, dementia), and the desirability of specific therapies may be further affected by social considerations and patient preferences. Therefore, the potential benefits and risks of each intervention must be carefully considered on an individualized basis. While elderly MI patients clearly represent a high-risk subgroup, it is important to recognize that they also comprise an extremely heterogeneous subgroup, and this heterogeneity has important therapeutic implications. For example, an 80-year-old patient

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presenting with a large anterior MI complicated by heart failure and hypotension has an expected mortality of over 50%. As a result, the potential benefit to be derived from maximally aggressive therapy (e.g., immediate catheterization and PCI) is large, thereby justifying a moderate increase in procedural risk. In contrast, an 80-year-old individual presenting with a small inferior MI of more than 12 hours’ duration who is hemodynamically stable and free of chest pain has a relatively favorable prognosis, and the risks associated with thrombolysis and PCI may not be justified. Thus, in considering the interventions described below, the clinician should keep in mind that the “sickest” patients often have the most to gain from aggressive treatment, while those with a more favorable prognosis often respond satisfactorily to conservative management. GENERAL MEASURES As in younger patients, the early management of older patients with acute MI should include measures designed to relieve the patient’s discomfort and treat any hemodynamic disturbances, such as heart failure or hypotension (Table 1). Morphine sulfate in doses of 2 to 4 mg intravenously is the recommended agent for treating chest pain in patients with Table 1 General Measures for the Early Management of Elderly Patients with Acute Myocardial Infarction Symptom or sign

Agent

Dose

Comment

Chest pain

Oxygen

2–5 L/min

Morphine

2–4 mg IV, q 5–15 min

Nitroglycerin

0.4 mg sublingually; 2% ointment, 1/2–2@ transdermally; 10–200 mg/min IV 2.5–5 mg IV, q 2–5 min, up to 15 mg

Probably not helpful if O2 saturation
92% Watch for respiratory depression Watch for hypotension, especially in inferior myocardial infarction

Metoprolol

Atenolol Congestive heart failure

Dobutamine

2.5–5 mg IV, q 10 min. up to 10 mg As needed to maintain arterial saturation
92% 20–80 mg IV 0.5–2 mg IV 2% ointment, 1/2–2@ transdermally; 10–200 mg/min IV As needed to maintain adequate perfusion 2.5–10 mg/kg/min

Dopamine Norepinephrine

2–40 mg/kg/min 0.5–30 mg/min

Oxygen Furosemide Bumetanide Nitroglycerin

Hypotension

IV fluids

Abbreviation: HF, heart failure.

Watch for bradycardia, hypotension, heart, block, bronchospasm, worsening HF

Watch for hypotension Watch for hypotension Avoid hypotension

Watch for worsening heart failure Watch for worsening hypotension; may aggravate ischemia May worsen ischemia May worsen ischemia

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acute MI (10). Empiric administration of supplemental oxygen is appropriate, but it is unlikely to improve tissue oxygen delivery if the baseline arterial saturation exceeds 92%. Nitroglycerin is safe in the majority of patients with acute MI, and it is effective in reducing myocardial oxygen demand when administered sublingually, transdermally, or intravenously. Nitrates can occasionally result in a precipitous fall in blood pressure, especially when given sublingually to patients with inferior MI associated with right ventricular involvement (11). Intravenous b-blockers are also effective in relieving chest pain, and both metoprolol and atenolol have been approved for use in patients with acute MI (12,13). As discussed below, contraindications to b-blockers include marked bradycardia, hypotension, moderate or severe heart failure, advanced atrioventricular (AV) block, and significant bronchospastic lung disease. Heart failure (HF) and hypotension are common complications of acute MI in the elderly, and each is discussed in more detail later in this chapter. They are mentioned briefly here because they are often present when the patient arrives in the emergency room and empiric therapy may be necessary. In most cases, HF occurring in the early stages of acute MI can be effectively treated with a combination of diuretics, nitrates, and supplemental oxygen. In patients who do not respond to these measures, further investigation into the etiology of HF is appropriate. Urgent echocardiography is the most useful noninvasive test in this setting, since it allows assessment of left and right ventricular function, valvular structures, and the pericardium. Sympathomimetic agents such as dobutamine and dopamine are best avoided in the early hours of acute MI because they increase myocardial oxygen demand and may worsen ischemia, but patients with severe HF, particularly when accompanied by hypotension, may require inotropic therapy. In the absence of supraventricular tachyarrhythmias, digitalis has little value in the management of HF associated with acute MI. Hypotension, particularly when accompanied by HF or impaired tissue perfusion, is a grave prognostic sign warranting prompt intervention. Hypotension without HF should be treated with IV fluids at a rate of 75 to 250 cc/hr until an adequate blood pressure has been restored or until signs of HF develop. In patients with inferior MI, hypotension associated with bradycardia may be due to heightened vagal tone and may respond to 0.5 to 1 mg of subcutaneous or IV atropine. Further investigation is required if the blood pressure fails to respond to fluid resuscitation and both noncardiac (e.g., sepsis, pulmonary embolism, medications) and cardiac causes of hypotension should be considered. In patients with persistent unexplained hypotension, the use of an inotropic or vasopressor agent may be necessary, but the precautions noted above should be borne in mind.

FIBRINOLYTIC THERAPY In the mid to late 1980s, a series of large randomized clinical trials demonstrated that IV administration of a fibrinolytic agent within 6 to 12 hours of symptom onset in patients with acute MI associated with ST-segment elevation or left bundle branch block led to a significant reduction in short-term and long-term mortality (14–18). These studies ushered in the reperfusion era and revolutionized the approach to treatment of patients with acute coronary syndromes. However, despite the fact that more than 20 years have elapsed since the publication of the first, large trial of fibrinolytic therapy (14), the value of this treatment in patients over age 75 remains controversial. In 1994, the Fibrinolytic Therapy Trialists’ (FTT) Collaborative Group published a meta-analysis of all major trials, including a subgroup analysis by age (Fig. 1) (19). Although the greatest absolute benefit was seen in patients 65 to 74 years of age (26 fewer

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Figure 1 Efficacy of fibrinolytic therapy by age. Source: From Ref. 19.

deaths per 1000 treated patients), the benefit was more modest in patients over age 75 years (10 fewer deaths per 1000 treated patients) and failed to achieve statistical significance. Reanalysis of the FTT data, limited to patients presenting within 12 hours of symptom onset with ST-segment elevation or left bundle branch block, showed that among patients aged 75 years or older, mortality was reduced from 29.4% to 26.0% (34 fewer deaths per 1000 treated patients, p ¼ 0.03) (20). Moreover, the absolute benefit was similar to that seen in other age groups, and greater than in patients younger than age 55. In contrast to the FTT analysis, several observational studies have suggested that the use of fibrinolytic therapy in patients over 75 years of age may be associated with adverse outcomes (21–23). In one study, Thiemann et al. examined outcomes in 7864 Medicare patients with acute MI who were suitable candidates for fibrinolytic therapy (21). Among patients 65 to 75 years of age, administration of a fibrinolytic agent was associated with reduced mortality, consistent with the randomized trials. However, among patients aged 76 to 86, mortality was 38% higher in those who received a fibrinolytic drug. In another study, also based on the Medicare database, Berger et al. found that 30-day mortality tended to be higher among patients over 75 years of age receiving fibrinolytic therapy, although the one-year mortality was lower (perhaps reflecting selection bias) (22). In another study, Soumerai et al. examined outcomes of fibrinolytic therapy at 37 Minnesota hospitals and found that fibrinolytic treatment was associated with a 40% higher mortality rate among patients 80 years of age or older (23). The findings of these studies are mitigated somewhat by a report from Stenestrand et al., who examined outcomes in 6891 patients aged 75 years or older hospitalized in Sweden with ST-segment elevation MI from 1995 to 1999 (24). Using propensity score analysis, these investigators found that patients who received fibrinolytic treatment had a 13% lower adjusted relative risk of death or nonfatal cerebral bleeding during a one-year follow-up period (p ¼ 0.001). Although the beneficial effects of fibrinolytic therapy were significant in patients 75 to 79 and 80 to 84 years of age, the absolute benefit was lower and no longer statistically significant among patients aged 85 years or older. One plausible explanation for the apparent discrepancy between the clinical trials and some of the community-based analyses is that criteria for fibrinolysis were strictly regulated in clinical trials, thus ensuring an optimal risk–benefit ratio. Nonadherence to

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these criteria in clinical practice may have led to overutilization of fibrinolytic agents in patients who were less-than-ideal candidates for such therapy, resulting in diminished benefit and increased complications. In summary, data from multiple randomized clinical trials demonstrate that fibrinolytic therapy is beneficial in appropriately selected elderly patients, including those over 75 years of age. However, observational studies indicate that caution is advised in the very elderly, and suggest that strict adherence to established criteria for use of fibrinolytic drugs is essential in patients over age 75 in order to maximize benefit and minimize risk (25). One factor that limits utilization of fibrinolytic therapy in elderly patients is concern about increased risk of bleeding, particularly intracranial hemorrhage. In the FTT overview of nine large fibrinolytic trials, strokes occurred in 1.2% of patients receiving a fibrinolytic agent, compared to 0.8% in control group patients (absolute difference 0.4%; p < 0.0001) (19), and the excess in strokes attributable to fibrinolysis increased with age. Thus, in patients over 75 years of age, the stroke rate was 2.0% in patients receiving fibrinolytic therapy, as compared with 1.2% in controls. Other serious bleeding complications, defined as either life-threatening or requiring transfusion, were relatively uncommon, occurring in 1.1% of patients over 75 years of age receiving fibrinolytic treatment, as compared with 0.5% of control group patients. Notably, the excess in major bleeding complications attributable to fibrinolysis was similar in older and younger patients. Thus, the absolute excess risk for both strokes and major bleeding is less than 1%. Nonetheless, caution is advised when using fibrinolytic agents in elderly patients at increased risk for stroke (e.g., those with prior cerebrovascular disease, severe uncontrolled hypertension, or a markedly increased arterial pulse pressure), as well as in patients at increased risk for serious bleeding (26–28). Several large trials have compared the effects of different fibrinolytic agents on clinical outcomes (29–32). In the Global Utilization of Streptokinase and tPA for Occluded Arteries (GUSTO)-I trial, which randomized over 40,000 acute MI patients to one of four fibrinolytic regimens, alteplase was associated with lower 30-day mortality than streptokinase in patients up to the age of 85 (32). However, the absolute benefit was small in patients over 75 years of age, and alteplase was associated with a significantly higher risk of intracranial hemorrhage (ICH) compared with streptokinase in this age group (2.1% vs. 1.2%; p < 0.05) (33). More recent studies with the newer fibrinolytic agents reteplase and tenecteplase failed to demonstrate a survival advantage of these agents compared with alteplase (34,35), and in the GUSTO-III trial, reteplase was associated with a higher rate of ICH than alteplase (2.5% vs. 1.7%) among patients over 75 years of age (34). Thus, currently available data indicate that the more fibrin-specific fibrinolytic agents (i.e., alteplase, reteplase, tenecteplase) are associated with increased risk of ICH compared with streptokinase in patients over age 75, and the merits of these agents with respect to other clinical outcomes, including mortality, have not been convincingly established in the very elderly. Streptokinase is administered in a dose of 1.5 million units intravenously over 1 hour, and no dosage adjustment is required for elderly patients. Alteplase should be administered as an initial bolus of 15 mg, followed by 0.75 mg/kg over 30 minutes (not to exceed 50 mg), and 0.5 mg/kg over the next 60 minutes (not to exceed 35 mg) (32). Reteplase is administered in two bolus doses of 10 units at an interval of 30 minutes (34). Tenecteplase is given as a single 30 to 50 mg bolus based on the weight of the patient (35). Aspirin 160 to 325 mg should be given to all patients receiving fibrinolytic therapy. Patients treated with alteplase, reteplase, or tenecteplase should also receive IV heparin to maintain the activated partial thromboplastin time (aPTT) in the range of 50 to 70 seconds

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for the first 24 to 48 hours (36,37). For patients treated with streptokinase, data from the GUSTO study indicate that IV heparin increases bleeding complications but does not improve survival relative to high dose subcutaneous heparin (12,500 U every 12 hours) (32).

PERCUTANEOUS CORONARY INTERVENTION PCI has several potential applications in the acute MI setting: as a primary reperfusion strategy; as an adjunct to thrombolysis; as a “rescue” procedure for failed thrombolysis; and in the management of recurrent ischemia (38,39). In several studies, PCI has been shown to be more effective than fibrinolytic therapy in recanalizing the infarct-related coronary artery, with reperfusion rates of over 90% in some series (39). In addition, three randomized trials suggest that PCI is associated with superior outcomes relative to fibrinolytic therapy in older patients with ST-elevation MI (40–42). deBoer et al. randomized 87 acute MI patients over 75 years of age to streptokinase or PCI. At 30 days follow-up, patients allocated to PCI had a reduced risk of death, reinfarction or stroke (p ¼ 0.01), and this benefit persisted for at least one year (40). In another study involving 130 patients with ST-elevation MI 70 years of age or older receiving tissue plasminogen activator or PCI, treatment with PCI was an independent predictor of lower mortality, reinfarction, or revascularization for recurrent ischemia at six months’ follow-up (41). In the largest trial reported to date, Grimes et al. randomized 481 patients aged 70 years or older presenting within 12 hours of onset of STelevation MI to fibrinolytic therapy or PCI (42). In this study, PCI was associated with a 55% reduction in death, stroke, or reinfarction relative to fibrinolysis (p ¼ 0.05). Of note, the benefit of PCI was limited to patients 70 to 79 years of age; among 131 patients aged 80 years or older, outcomes did not differ between reperfusion strategies. The findings of these studies are also supported by subgroup analysis from a systematic overview of 22 randomized trials comparing PCI with fibrinolytic therapy in 6763 patients with acute MI (38). Overall, PCI was associated with a significant 37% reduction in 30-day mortality, and the absolute benefit was greater in patients over age 65 than in younger patients. Moreover, the absolute benefit of PCI increased progressively with age, from 1.0% in patients less than 65 years to 4.2%, 5.1%, and 6.9% in patients of ages 65 to 74, 75 to 84, and 85 or older, respectively (25). In summary, current data suggest that PCI can be performed safely in elderly patients with acute MI and that it is associated with fewer hemorrhagic strokes and more favorable clinical outcomes compared to fibrinolysis (25). Although present data are insufficient to allow definitive conclusions on primary PCI versus fibrinolytic therapy in patients over 80 years, PCI is an effective therapeutic option in appropriately selected patients and should be strongly considered when fibrinolytic therapy is contraindicated (10,25). In particular, very high-risk elderly patients, such as those with large anterior MIs or severe hemodynamic disturbances, may be most likely to benefit from this approach (43). The routine use of PCI following fibrinolysis was evaluated in several trials prior to the era of intracoronary stents and none of these studies demonstrated improved outcomes relative to conservative management (44–49). In contrast, two more recent trials reported favorable outcomes among patients who underwent routine stent implantation following fibrinolysis compared with conservative management (50,51). Both of these studies were relatively small and primarily involved younger patients with no subgroup analysis by age. Therefore, the role of routine PCI following successful fibrinolysis in older patients remains uncertain.

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Patients who experience recurrent ischemic pain or marked ST-segment changes on a predischarge stress test are at high risk for recurrent ischemic events following hospital discharge. Coronary angiography and revascularization with either PCI or coronary bypass surgery is appropriate in these patients (52) and age per se is not a contraindication to these procedures (10,25,38). Patients with persistent ischemic pain following administration of a fibrinolytic agent, particularly when accompanied by hemodynamic instability (e.g., hypotension or marked HF), are also at high risk for adverse outcomes, and “rescue” PCI appears to improve prognosis in this subgroup (38,39,53,54). Thus, although cardiac catheterization and revascularization are not recommended as routine procedures for all older patients with acute ST-segment elevation MI, they should be strongly considered in patients with persistent chest pain, marked hemodynamic instability, or recurrent ischemia in the early post-MI period (10,25). ANTITHROMBOTIC AGENTS Aspirin Aspirin is of proven benefit in patients with either unstable angina (55,56) or acute MI (16) and it should be considered standard therapy in all patients presenting with acute coronary syndromes (ACS) in the absence of major contraindications. Evidence supporting the use of aspirin for acute MI derives from the second International Study of Infarct Survival (ISIS-2), in which 17,187 patients with suspected MI were randomized to receive either aspirin 162.5 mg or placebo, and either streptokinase 1.5 million units or placebo (16). Overall, patients receiving aspirin experienced a 23% reduction in the risk of vascular death within 35 days of hospitalization, and this effect was independent of whether or not the patient received streptokinase. In 3411 patients over 70 years of age, aspirin was associated with a 21% reduction in vascular deaths (17.6% vs. 22.3%; p < 0.01) (16). With respect to aspirin dosage, available evidence suggests that the minimum effective dose in patients with acute MI is 160 mg, and that doses in excess of 325 mg provide no additional benefit (57). Importantly, the initial dose of aspirin should be administered as soon as possible after presentation, and the nonenteric-coated form should be used to ensure rapid absorption. When possible, the first dose should be chewed rather than swallowed. Following MI, aspirin should be continued indefinitely at a dose of 75 to 325 mg daily or every other day (58,59). Heparin Subcutaneous heparin in a dose of 7500 U every 12 hours reduces the risk of venous thromboembolic complications in patients hospitalized with acute MI (60). Since older patients are at increased risk for deep vein thrombosis and pulmonary embolism, prophylaxis against these events is appropriate in this age group. At present, the value of routine IV heparin for all patients with acute ST-elevation MI remains unproven (61), but several subgroups do appear to benefit (10,62). Patients with large anterior MIs, acute or chronic atrial fibrillation, or severe left ventricular dysfunction with congestive heart failure are at increased risk for mural thrombus formation and embolization. Intravenous heparin at doses adjusted to maintain the aPTT at 1.5 to 2 times the control value appears to reduce arterial thromboembolism in patients with large anterior MIs (60,62,63), and routine heparinization is appropriate (10). Patients with atrial fibrillation should be anticoagulated with heparin or warfarin, but the value of systemic anticoagulation in patients with severe left ventricular dysfunction is unproven,

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and its use in this situation should be individualized (10). Patients who experience recurrent ischemia during the first few days after MI are at increased risk for infarct extension, and IV heparin is recommended (10,60).

Low-molecular-weight Heparin Compared with unfractionated IV heparin, low-molecular-weight heparins (LMWHs) offer several advantages: once or twice daily subcutaneous dosing, no need to monitor aPTTs, and fewer side effects (especially thrombocytopenia). In a meta-analysis of 14 trials involving 25,280 patients with ST-elevation MI receiving fibrinolytic therapy and aspirin, Eikelboom et al. reported that relative to placebo, LMWH reduced the risk of reinfarction by 28% and death by 10%, but increased the risk of major bleeding and intracranial bleeding (64). Compared with unfractionated heparin, LMWH reduced the risk of reinfarction by 45%, increased the risk of minor bleeding, and had no effect on mortality or major bleeding. Subgroup analyses by age were not reported. In addition, since all patients in these trials were treated with a fibrinolytic agent, the findings may not be applicable to patients receiving PCI or no reperfusion therapy. Further, careful attention to dosing of LMWH is required in older patients with decreased renal function, since excess dosing has been associated with an increased risk for major bleeding. (65) Based on available data, current guidelines recommend unfractionated heparin in preference to LMWH in patients with ST-elevation MI undergoing reperfusion therapy with either PCI or a fibrinolytic agent (10). In other patients for whom antithrombotic therapy is warranted, either unfractionated heparin or LMWH may be used.

Glycoprotein llb/llla Inhibitors The glycoprotein (GP) Ilb/IIIa inhibitors are potent antiplatelet agents that block the final common pathway leading to platelet aggregation. Three GP IIb/IIIa inhibitors— abciximab, eptifibatide, and tirofiban—have been shown to improve outcomes in patients with ACS, primarily in the setting of non-ST-elevation MI (66–70). However, although the benefits of GP IIb/IIIa inhibitors in patients up to the age of 75 years are similar to those in younger patients, the value of these agents in older patients is less clear. For example, in a trial involving over 10,000 patients, eptifibatide reduced the risk of death or nonfatal MI in patients up to the age of 79, but there was an increase in event rates among patients over 80 years of age receiving eptifibatide (70). In another study involving a smaller number of patients (n ¼ 1915), tirofiban was associated with improved outcomes in patients younger or older than age 65, but outcomes for patients over 75 years were not reported (69). More recently, a retrospective analysis from the Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment (ISAR-REACT) trial found that although abciximab reduced the risk of major coronary events by 43% in ACS patients under age 70 undergoing PCI, there was no benefit in patients age 70 or older (71). Nonetheless, on the basis of current evidence, the addition of abciximab to aspirin and heparin is recommended for patients with acute ST-elevation MI undergoing cardiac catheterization and PCI (10). In patients with STelevation MI not undergoing PCI, routine use of GP IIb/IIIa inhibitors is not recommended (10). Furthermore, the risk of bleeding complications associated with these agents increases with age, which may negate the clinical benefit of GP IIb/IIIa inhibitors in the very elderly.

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Thienopyridines Ticlopidine and clopidogrel are thienopyridine derivatives that inhibit platelet aggregation through multiple mechanisms; both are more effective antiplatelet agents than aspirin. Although both drugs reduce restenosis rates following coronary stent implantation, clopidogrel is preferred because of superior efficacy and safety (72). In addition, the combination of clopidogrel and aspirin has been shown to reduce the risk of cardiovascular death, MI, or stroke by about 20% compared to aspirin alone during the 12-month period following hospitalization for unstable angina or non-ST-elevation MI, with similar absolute benefits in patients younger or older than age 65 (73). Current guidelines recommend clopidogrel for all patients with ACS undergoing PCI (10). Clopidogrel should be continued for at least one month following placement of a bare metal stent and for at least 9 to 12 months following placement of a drug-eluting stent. If feasible, clopidogrel should be discontinued five to seven days prior to coronary bypass surgery because of an increased risk for perioperative bleeding. Warfarin Long-term anticoagulation with warfarin has been shown to reduce the risk of reinfarction and cardiac death in post-MI patients, including the elderly (74–76), and recent studies indicate that warfarin, with or without aspirin, is superior to aspirin alone (77,78). However, the addition of warfarin to aspirin increases the risk of bleeding, and this risk is greatest in elderly patients. Current indications for warfarin in the post-MI setting include allergy to aspirin, chronic or paroxysmal atrial fibrillation, the presence of a mechanical prosthetic heart valve, or active thromboembolic disease. Anticoagulation for a minimum of three months is also recommended for patients with a left ventricular mural thrombus following acute MI (10). Warfarin may also be considered in other patients deemed to be at high risk for left ventricular thrombus or recurrent coronary events. Bleeding Complications An important consideration when using antithrombotic therapy in older patients is the increased bleeding risk accompanying the administration of multiple antithrombotic agents (e.g., aspirin, heparin, clopidogrel, and a glycoprotein IIb/IIIa inhibitor). Although there is no precise method to quantify this risk and to accurately assess the risk–benefit ratio of using multiple antithrombotic drugs in an individual patient, it is worth noting that in a recent study to evaluate the effects of LMWH and abciximab (a glycoprotein IIb/IIIa inhibitor) in patients receiving tenecteplase for acute MI, abciximab was associated with a marked increase in bleeding complications among patients over 75 years of age, resulting in overall worse outcomes in this age group (79). In addition, advanced age has been associated with increased risk for excessive dosing and major bleeding complications in patients with ACS treated with heparin, LMWH, or GP IIb/IIIa inhibitors (65). Thus, the benefits of aggressive antithrombotic therapy in reducing recurrent ischemic events must be carefully balanced against the risk of serious bleeding complications, particularly in the very elderly. b-BLOCKADE Most of the major trials evaluating b-blockers for the treatment of acute MI were conducted prior to the reperfusion era. However, since most elderly patients with acute MI do not undergo primary PCI or thrombolysis (80,81), the results of these earlier trials remain applicable.

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Table 2 Mortality in Three Large Trials of Intravenous b-Blockade Mortality (%)

Atenolol ISIS-1 (12)a <65 yr
65 yr Metoprolol Goteborg (82)a <65 yr 65–74 yr MIAMI (13)a <60 yr 61–74 yr Pooled totals Younger Older

Number

Active

Control

Difference

% Change

p value

16,027 10,805 5,222

2.5 6.8

2.6 8.8

0.1 2.0

4.0 22.7

NS 0.001

4.5 8.1

5.7 14.8

1.2 6.6

21.1 45.0

NS 0.03

1.9 6.8

1.8 8.2

þ0.1 1.5

þ3.1 17.8

NS NS

2.5 6.9

2.6 8.9

0.1 2.1

5.0 23.2

NS 0.0005

1,395 917 478 5,778 2,965 2,813 23,200 14,687 8,513

a

Reference. Abbreviations: ISIS-1, First International Study of Infarct Survival; MIAMI, Metoprolol in Acute Myocardial Infarction; NS, not significant.

Table 2 summarizes data from three large randomized trials of early IV b-blockade in patients with suspected MI (12,13,82). In the ISIS-1 study, administration of IV atenolol followed by oral therapy was associated with a 15% reduction in vascular deaths within the first seven days (12). Among 5222 patients 65 years of age or older, there was a 23% mortality reduction (p ¼ 0.001) (12). Similarly, in two trials using IV metoprolol, older patients benefited more than younger patients (13,82). In pooling the results of these three trials, mortality was reduced by 23% in older patients ( p ¼ 0.005), but by only 5% in younger patients (p ¼ not significant). These data clearly indicate that older patients, who are at higher risk for adverse outcomes, derive proportionately greater benefit from early b-blocker therapy than younger patients. As a result, IV b-blockers should not be withheld on the basis of age. The value of IV b-blockade in combination with fibrinolytic therapy was assessed in the second Thrombolysis in Myocardial Infarction trial (TIMI-II) (83,84). In this study, 1434 patients with acute MI were treated with alteplase and then randomized to receive IV metoprolol or placebo. Although there was no difference in hospital or six-week mortality, patients receiving metoprolol experienced significantly fewer nonfatal ischemic events during follow-up. These findings provide support for the use of early IV b-blockade as an adjunct to fibrinolysis in patients with acute MI. More recently, Wienbergen et al. examined the impact of early b-blocker therapy in 17,809 consecutive patients with ST-elevation MI enrolled in the German Maximal Individual Therapy of Acute Myocardial Infarction PLUS (MITRA PLUS) registry (85). After adjusting for covariates, early b-blocker treatment was associated with a 30% lower hospital mortality, and the greatest benefit was seen in high-risk patients, including those over age 65. Despite these favorable results, recently reported findings from the Clopidogrel and Metoprolol in Myocardial Infarction Trial (COMMIT) have raised new questions about the value of IV b-blockers in patients with acute MI (86). In this study, 45,852 patients with acute MI, 93% of whom had ST-elevation or left bundle branch block, were

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randomized to IV metoprolol or placebo. Overall, metoprolol did not reduce the risk of death, reinfarction, or cardiac arrest, but the risk of cardiogenic shock was increased by 30% in patients randomized to metoprolol. Among 11,934 patients aged 70 years or older enrolled in the trial, hospital mortality was 13.6% with metoprolol compared with 13.3% in the placebo group. Current guidelines recommend prompt administration of an oral b-blocker to all patients with acute MI in the absence of contraindications (10). Intravenous b-blocker therapy may be considered in stable patients with tachycardia or hypertension who have no contraindication to b-blocker therapy. The long-term use of b-blockers for secondary prevention following acute MI has been extensively investigated, and Table 3 summarizes data from three of the largest and most frequently cited trials (82,87–91). Notably, reductions in mortality and reinfarction during long-term therapy were at least as great in the elderly as in younger patients. More recently, carvedilol was associated with a 23% reduction in mortality relative to placebo in patients with a left ventricular ejection fraction less than or equal to 40% following acute MI (92). In addition, observational studies indicate that the survival benefits of b-blockers following MI appear to extend to patients over 75 years of age (93–95). In one study, covariate-adjusted two-year mortality rates in patients prescribed b-blockers, relative to those who were not, were 50% lower among patients 65 to 74 years of age, 44% lower in patients age 75 to 84, and 28% lower in patients over age 85 (93). b-Blockers are also highly cost-effective in all age groups (96). Thus, b-blockers are recommended for all patients following acute MI in the absence of contraindications. At the present time, only atenolol and metoprolol have been approved for IV use in the acute MI setting. The recommended dose for intravenous atenolol is two 5 mg boluses at an interval of 10 minutes. Oral atenolol 50 mg every 12 hours should be initiated 10 minutes after the second IV dose. For metoprolol, the recommended IV dose is 15 mg (three 5 mg doses at 2 minute intervals). Oral metoprolol 25 to 50 mg every 6 hours should be started 15 minutes after the last IV dose, progressing to 100 mg twice daily in Table 3 Mortality in Three Large Trials of Long-term b-Blockade Mortality (%)

Propranolol BHAT (87,88)a 30–59 yr 60–69 yr Timolol Norwegian (89,90,91)a <65 yr 65–75 yr Metoprolol Goteborg (82)a <65 yr 65–74 yr Pooled totals Younger Older a

Number

Active

Control

Difference

% Change

p value

3,837 2,588 1,249

6.0 9.7

7.4 14.7

1.4 5.0

18.7 33.7

NS 0.01

1,884 1,149 735

5.0 8.0

9.7 15.3

4.7 7.3

48.3 47.8

0.003 0.003

4.5 8.1

5.7 14.8

1.2 6.6

21.1 45.0

NS 0.03

5.5 8.9

7.6 14.9

2.2 6.0

28.3 40.1

0.004 0.0001

1,395 917 478 7,116 4,654 2,462

Reference. Abbreviations: BHAT, b-Blocker Heart Attack Trial; NS, not significant.

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24 to 48 hours. In very elderly patients, it may be advisable to reduce the dosages of both the agents. Contraindications to the use of IV b-blockers include marked sinus bradycardia (heart rate < 45/min), systolic blood pressure less than 100 mmHg, marked first-degree AV block (PR interval
0.24 seconds) or higher levels of block, moderate or severe HF, active wheezing, or a history of significant bronchospastic pulmonary disease. Mild HF and chronic lung disease without bronchospasm are not contraindications to b-blocker therapy. Propranolol, metoprolol, timolol, and carvedilol have all been approved for longterm use following MI. Recommended daily dosages for these agents are as follows: propranolol 180 to 240 mg, metoprolol 200 mg, timolol 20 mg, and carvedilol 50 mg. Elderly patients may require lower doses to avoid adverse effects, and there are data suggesting that lower doses may be as effective as higher ones for reducing mortality in older patients (97). Contraindications to oral b-blockers are similar to those listed for the IV drugs. NITRATES Nitrates are widely used in the treatment of acute MI (98), but two large studies (GISSI-3 and ISIS-4) failed to confirm a beneficial effect when nitrates were initiated within 24 hours of MI onset (99,100). However, among 5234 patients aged 70 years or older enrolled in GISSI-3, the combined endpoint of death or severe left ventricular dysfunction at 6 months follow-up was significantly reduced by nitroglycerin (odds ratio 0.88; p ¼ 0.04) (101). This finding, coupled with the fact that both GISSI-3 and ISIS-4 demonstrated that nitrates can be administered safely to the majority of older patients, suggests that the continued use of nitrates for treating ischemic pain and peri-infarctional heart failure is appropriate. Routine use of nitrates in elderly patients without pain or pulmonary congestion is of unproven value. Nitrates are contraindicated in patients with right ventricular infarction or systolic blood pressure less than 90 mmHg in the setting of acute MI (10).

CALCIUM ANTAGONISTS Calcium channel blockers have been widely studied in both the acute MI and post-MI settings (102,103). At present, there is no evidence that treatment with calcium antagonists is beneficial in patients with acute MI, and the use of short-acting calcium antagonists may be harmful (102). One relatively small study showed that diltiazem 60 to 90 mg q.i.d. initiated 24 to 72 hours after admission for non-ST-elevation MI reduced the rate of reinfarction during short-term follow-up, but there was no effect on mortality (104). In another study, long-term diltiazem administration following MI did not affect overall mortality, but a modest benefit was seen in the subgroup of patients with preserved left ventricular function and no HF (105). Similar results have been reported with longterm verapamil use in post-MI patients (106), although a later study failed to confirm these findings (107). Thus, calcium antagonists are not recommended for routine use in acute MI patients, but administration of diltiazem or verapamil is reasonable in patients with preserved ventricular function and no HF who are not candidates for b-blockade (10). Calcium channel blockers are contraindicated in patients with acute MI complicated by heart failure or left ventricular systolic dysfunction.

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ANGIOTENSIN CONVERTING ENZYME INHIBITORS Early administration of an ACE inhibitor to acute MI patients has been evaluated in several large trials. The first of these, Cooperative New Scandinavian Enalapril Survival Study (CONSENSUS-2), was discontinued after 6000 patients were enrolled due to a higher frequency of adverse outcomes in patients receiving IV enalapril (108). Moreover, patients over 70 years of age experienced an increased incidence of serious hypotension. In contrast, the GISSI-3 and ISIS-4 trials reported small but statistically significant reductions in mortality in patients receiving oral captopril or lisinopril within 24 hours of MI onset (99,100). In addition, patients 70 years or older treated with lisinopril in GISSI-3 experienced a 14% reduction in the combined endpoint of death or severe left ventricular dysfunction at 6 months follow-up (p ¼ 0.01) (101). More recently, the Survival of Myocardial Infarction Long-term Evaluation (SMILE) investigators randomized 1556 patients with anterior MI who were not candidates for fibrinolytic therapy to either the ACE inhibitor zofenopril or to placebo within the first 24 hours after symptom onset (109). The incidence of death or severe heart failure at 6 weeks follow-up was reduced 34% by zofenopril, and this benefit was maintained for one year. Moreover, the absolute benefit was threefold greater in individuals over 65 years of age compared with younger patients (109). The applicability of the above findings to the general MI population is unclear, since the small benefit seen in the largest trials (absolute mortality reduction less than 1%) (99,100) may reflect a larger benefit in some patients (e.g., those with anterior MI or significant left ventricular dysfunction), but no benefit or even harm in other subgroups. At the present time, early administration of an oral ACE inhibitor is recommended in hemodynamically stable patients with anterior MIs, as well as in patients with HF or a left ventricular ejection fraction of less than 40% in the absence of hypotension (systolic blood pressure < 100 mmHg) or other contraindications (10). In other cases, early ACE inhibitor therapy is optional (10). The value of ACE inhibitors in post-MI patients with significant left ventricular dysfunction (ejection fraction < 40%) or clinical HF has been well established by the Salvage and Ventricular Enlargement (SAVE) (110) and Acute Infarction Ramipril Efficacy (AIRE) trials (111,112). In SAVE, captopril reduced mortality and the occurrence of other cardiac events during an average follow-up of 42 months in asymptomatic or minimally symptomatic patients with left ventricular dysfunction after MI (ejection fraction  40%) (110). In AIRE, ramipril produced similar effects in post-MI patients with clinical heart failure (111,112). Therapy was initiated 3 to 16 days after MI in SAVE (mean, 11 days), and 2 to 10 days after MI in AIRE (mean, 5 days). The maximum dose of captopril in SAVE was 50 mg t.i.d., while the target dose of ramipril in AIRE was 5 mg b.i.d. Importantly, in both SAVE and AIRE, the beneficial effects of therapy were most pronounced in elderly patients (110,111). In 783 patients over 65 years of age enrolled in SAVE, mortality was reduced by 23% with captopril (27.9% vs. 36.1%; p ¼ 0.017); by comparison, patients under age 65 experienced a statistically insignificant 9% mortality reduction (16.6% vs. 18.3%) (110). Similarly, ramipril significantly decreased mortality in patients over age 65 enrolled in AIRE, but not in younger patients (111). The Heart Outcomes Prevention Evaluation (HOPE) study also showed that the ACE inhibitor ramipril in a dose of 10 mg once daily reduced mortality and major vascular events in a broad range of patients 55 years of age or older with established vascular disease (including chronic coronary artery disease) or diabetes (113). Similarly, the European trial on reduction of cardiac events with perindopril in stable coronary artery disease (EUROPA) randomized 13,655 patients with stable coronary artery disease, of

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whom 64% had prior MI, to perindopril or placebo (114). After a mean follow-up period of 4.2 years, perindopril was associated with a 20% reduction in cardiovascular death, MI, or cardiac arrest, and the benefits were similar in younger and older patients. These findings are also supported by a retrospective analysis of 14,129 patients 65 years of age or older hospitalized with acute MI (115). In this study, patients discharged on an ACE inhibitor had a covariate-adjusted one-year mortality rate that was 15% lower than in patients not receiving an ACE inhibitor, including a 27% lower mortality in patients over the age of 80. In summary, ACE inhibitors are indicated for all patients following acute MI, including the elderly, in the absence of contraindications (10). The therapy should be initiated within the first few days in hemodynamically stable patients, but may be deferred in other cases. Dosages should be titrated to those proven to be effective in clinical trials, while monitoring blood pressure, renal function, and serum potassium levels at regular intervals. ANGIOTENSIN RECEPTOR BLOCKERS Angiotensin receptor blockers (ARBs) bind to the angiotensin1 (AT1) receptor on the cell membrane, thereby inhibiting the effects of angiotensin II. ARBs are associated with less cough than ACE inhibitors, but the rates of hyperkalemia and worsening renal function are similar with both drug classes. Two large trials have evaluated ARBs in the post-MI setting. In the Optimal Trial in Myocardial Infarction with Angiotensin II Antagonist Losartan (OPTIMAAL), patients 50 years of age or older with acute MI accompanied by heart failure, anterior Q waves on ECG, or an ejection fraction less than 35% were randomized to losartan or captopril and followed for an average of 2.7 years (116). Mortality was nonsignificantly higher in the losartan group (18.2% vs. 16.4%, p ¼ 0.069), with similar outcomes in older and younger subjects. In the Valsartan in Acute Myocardial Infarction Trial (VALIANT), 14,703 patients with acute MI were randomly assigned to receive captopril, valsartan, or both the drugs and followed for a median of 25 months (117). Mortality was similar in all three arms, but side effects and withdrawals were more common in patients randomized to combination therapy. More than half of the patients in VALIANT were 65 years of age or older, 3160 patients were aged 75 years or older, and outcomes with respect to the three treatment groups were similar across age categories, including patients over age 85 (118). On the basis of currently available evidence, ACE inhibitors remain the preferred agents in patients with recent acute MI, including the elderly (10). ARBs are indicated in patients with HF or left ventricular systolic dysfunction who are intolerant to ACE inhibitors. In addition, combination therapy with an ACE inhibitor and an ARB may be considered in patients with persistent symptomatic HF and an ejection fraction less than 40%. ALDOSTERONE ANTAGONISTS In the Eplerenone Post-acute myocardial infarction Heart Failure Efficacy and Survival Study (EPHESUS), the selective aldosterone antagonist eplerenone reduced mortality by 17% in patients with left ventricular dysfunction (ejection fraction  40%) and HF after myocardial infarction (119). However, the benefit of eplerenone was attenuated in patients 65 years of age or older, and there was no apparent benefit in patients aged 75 years or older. In addition, the risk of hyperkalemia was higher in older subjects. Therefore, the value of eplerenone in elderly patients following acute MI remains unproven (25).

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MAGNESIUM Although several relatively small studies suggested that selected patients with acute MI, including the elderly, might benefit from routine administration of magnesium (120,121), two large randomized trials failed to confirm a beneficial effect (100,122). Therefore, the routine use of IV magnesium in elderly patients with acute MI is not recommended (10). ANTIARRHYTHMIC AGENTS AND DEVICES The administration of prophylactic lidocaine to patients with acute MI was once a common practice. However, a meta-analysis suggested that lidocaine does not improve survival and may increase the incidence of asystolic cardiac arrest (123). Moreover, elderly patients hospitalized with acute MI appear to be at lower risk for primary ventricular fibrillation than younger patients (124), and toxicity from lidocaine is more common in the elderly. Thus, the routine use of lidocaine in elderly patients with acute MI is not recommended (10). Intravenous amiodarone is more effective than lidocaine in the treatment of lifethreatening ventricular arrhythmias in the setting of acute ischemic heart disease, and two trials have addressed the role of prophylactic oral amiodarone in the treatment of high-risk post-MI patients (125,126). In these studies, which involved a total of 2688 patients, amiodarone reduced the incidence of arrhythmic death by 35% to 38%, but there was no difference in total mortality. In one study, the absolute reduction in arrhythmic deaths was greatest in patients over 70 years of age (126). A subsequent meta-analysis, based on data from 13 amiodarone trials, found that amiodarone was associated with a 13% reduction in total mortality (p ¼ 0.03) and a 29% reduction in arrhythmic deaths ( p ¼ 0.0003) (127). In patients over 65 years of age, amiodarone reduced arrhythmic deaths by 32%, but total mortality was reduced by only 8% (not significant) (127). Based on amiodarone’s apparent lack of efficacy for reducing total mortality and the high side effect profile associated with this drug, prophylactic use of amiodarone in high-risk patients following acute MI is not recommended. An implantable cardioverter-defibrillator (ICD) is indicated in patients who develop ventricular fibrillation or hemodynamically significant sustained ventricular tachycardia more than 48 hours after acute MI (10). The value of prophylactic ICD insertion in other post-MI patients is uncertain because of conflicting results from clinical trials (128–130). In the most recent study, 674 patients with a left ventricular ejection fraction less than or equal to 35% and evidence for impaired cardiac autonomic function were randomized to receive an ICD or no ICD 6 to 40 days after acute MI (130). Although ICD implantation reduced the risk of arrhythmic death by 58%, there was no difference in total mortality during a mean follow-up period of 30 months. Thus, routine implantation of an ICD in post-MI patients is not warranted at the present time. Ongoing studies should clarify whether ICDs are beneficial in selected patients following MI, including the elderly. STATINS Statins have been shown to reduce long-term mortality and morbidity in patients up to 85 years of age with vascular disease (131,132). In addition, early administration of highdose statin therapy within the first 96 hours of acute MI has been shown to reduce the risk of recurrent ischemic events during the 4-month period following hospital discharge, with similar effects in older and younger patients (133). More recently, the Pravastatin or

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Atorvastatin Evaluation and Infection Therapy (PROVE-IT) trial demonstrated that highdose atorvastatin was more effective than standard dose pravastatin in reducing the composite endpoint of death, MI, hospitalization for unstable angina, coronary revascularization, or stroke following acute MI (134). The benefit of high-dose atorvastatin appeared to be limited, however, to patients less than 65 years of age. In another trial, early initiation of simvastatin 40 mg with a subsequent increase to 80 mg did not significantly improve outcomes relative to deferred treatment with simvastatin 20 mg in 4497 patients hospitalized with ACS, and the results were similar in younger and older patients (135). On the basis of the totality of evidence, prescription of statin therapy is recommended for all patients with acute MI regardless of age or baseline lipid profile (10,25).

MANAGEMENT OF COMPLICATIONS Elderly patients are at increased risk for several major complications of acute MI, including HF, hypotension, supraventricular arrhythmias, conduction disturbances, myocardial rupture, and cardiogenic shock. In general, the management of these complications is similar in older and younger patients. In the following sections, the treatment of each of these complications is briefly reviewed, with special attention to the elderly. Heart Failure Several factors predispose the elderly patient with acute MI to the development of HF, including an increased incidence of prior MI, higher prevalence of multivessel disease, impaired diastolic relaxation, reduced contractile reserve, and an increased prevalence of comorbid illnesses, both cardiac (e.g., aortic stenosis) and noncardiac (e.g., renal insufficiency) (136). As a result, HF occurs in approximately 50% of older patients with acute MI (7), and HF is often the presenting manifestation of MI in the elderly (137). The initial treatment of HF includes supplemental oxygen, diuretics, and nitrates. In more severe cases, morphine should also be given. Once therapy has been initiated, it is essential to determine the etiology of HF, which is frequently multifactorial in elderly patients. Commonly occurring factors that may contribute to HF in the elderly include persistent or recurrent ischemia, extensive myocardial damage, aortic or mitral valve disease (especially aortic stenosis or mitral regurgitation), arrhythmias (especially atrial fibrillation), uncontrolled hypertension, diastolic dysfunction due to left ventricular hypertrophy, inappropriate bradycardia, mechanical complications (e.g., papillary muscle rupture or ventricular septal perforation), severe renal insufficiency, and medications (e.g., b-blockers, calcium antagonists, and antiarrhythmic agents). In most cases, an echocardiogram with Doppler studies, in conjunction with a careful review of the patient’s medications and laboratory data, will be sufficient for determining the pathogenesis of HF (10). Occasionally, supplemental studies, such as pulmonary artery catheterization or left ventricular angiography, may be necessary (10). Once the etiology has been established, an effort should be made to correct treatable disorders and to reduce the dose or discontinue offending medications. If HF persists despite aggressive diuresis, placement of a pulmonary artery catheter should be considered as an aid to diagnosis and therapy. When indicated, treatment with an inotropic agent and/or an IV vasodilator should be instituted. Dobutamine is the most frequently used IV inotrope for treating severe left ventricular dysfunction, but dobutamine

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may be less effective in the elderly due to an age-related decline in b-adrenergic responsiveness (138,139). Phosphodiesterase inhibitors such as milrinone have theoretical advantages over sympathomimetic agents in coronary patients because they augment cardiac output without increasing myocardial oxygen demand (140). Nonetheless, in elderly patients with severe HF without recent MI, dobutamine appears to be at least as effective as a phosphodiesterase inhibitor (141). Nitroglycerin, nitroprusside, and nesiritide are the most commonly used IV vasodilators, but nitroglycerin is the only one recommended for treatment of HF in the setting of acute MI (10). Intravenous nitroglycerin has a very short half-life, which allows rapid drug titration. Hypotension is the most common serious adverse effect, so blood pressure should be monitored closely. In patients with acute decompensated HF, nesiritide is more effective than nitroglycerin in relieving pulmonary congestion and reducing dyspnea (142), but data on the use of nesiritide in patients with acute MI are very limited, and there is concern that nesiritide may be associated with worsening renal function and increased short-term mortality (143,144). Intravenous enalaprilat is another alternative to nitroglycerin and may be useful in patients who are likely to require long-term ACE inhibition. However, enalaprilat may also induce hypotension and renal dysfunction, and it offers no clear advantage over conventional agents in the acute MI setting (145). Patients who fail to respond to the above measures have refractory HF, and the prognosis is grave unless a correctable problem, such as a ventricular aneurysm, can be identified. Additional interventions that may help stabilize patients with refractory HF include endotracheal intubation with assisted ventilation and placement of an intra-aortic balloon pump. Such therapies are usually appropriate only in patients with potentially reversible pathology. Hypotension Hypotension in the setting of acute MI usually reflects a low cardiac output state arising from extensive myocardial damage, intravascular volume depletion, right ventricular infarction, valvular dysfunction (especially mitral regurgitation), pericardial effusion, or arrhythmias (both tachycardias and bradycardias). Other factors that may contribute to hypotension in elderly patients include preexisting cardiac conditions such as aortic stenosis or cardiomyopathy, ventricular septal perforation, aortic dissection, sepsis, bleeding (e.g., from fibrinolytic therapy or catheterization), and medications. The cause of hypotension is frequently multifactorial, and it is incumbent upon the physician to consider all potential etiologies and to perform appropriate diagnostic investigations as indicated. If the history, physical examination, and laboratory data fail to provide an explanation, echocardiography should be performed promptly (10). If hypotension persists or if the etiology remains unexplained, pulmonary artery catheterization is indicated (10). In the absence of HF, intravascular volume expansion is the appropriate initial treatment for hypotension. Subsequent therapy will depend on the response to fluid administration and the underlying etiology. Patients who fail to respond to IV fluids or who have coexistent HF may require pulmonary artery catheterization (10). On the basis of the hemodynamic findings and the severity of hypotension, treatment with sympathomimetic agents such as dobutamine, dopamine, or norepinephrine may be necessary to maintain organ perfusion. Other supportive measures include assisted ventilation and intra-aortic balloon counterpulsation (10). It is important to emphasize that all of these interventions are palliative, and unless the underlying etiology of hypotension can be corrected, the prognosis is grave.

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Arrhythmias and Conduction Disturbances Elderly patients with acute MI are at increased risk for supraventricular arrhythmias, particularly atrial fibrillation, and for conduction disturbances, including bundle branch block and high-degree AV block. The incidence of ventricular tachycardia is similar in older and younger patients, but primary ventricular fibrillation occurs less frequently in the elderly (124), possibly reflecting reduced b-adrenergic responsiveness in this age group. New-onset atrial fibrillation following acute MI usually results from atrial distension due to an increase in ventricular diastolic pressure. Contributing factors may include mitral or tricuspid regurgitation, atrial infarction, pericarditis, electrolyte abnormalities (particularly hypokalemia), and medications (e.g., inotropic agents, bronchodilators). Because elderly patients frequently have preexisting diastolic dysfunction and an increased reliance on atrial contraction to augment ventricular filling (the “atrial kick”) (136), atrial fibrillation often precipitates HF or a low cardiac output state. Treatment of atrial fibrillation includes correcting any reversible abnormalities (e.g., hypokalemia), controlling the ventricular rate, and restoring sinus rhythm. In patients who are hemodynamically stable, rate control with b-blockers or rate-lowering calcium channel blockers (i.e., diltiazem or verapamil) is appropriate. In most cases, heparinization to maintain the activated partial thromboplastin time (aPTT) in the range of 50 to 70 seconds is also indicated. Although effective rate control often results in spontaneous conversion to sinus rhythm, if atrial fibrillation persists longer than 24 hours, pharmacological or electrical cardioversion should be considered. Antiarrhythmic agents commonly used in the cardioversion of recent-onset atrial fibrillation include amiodarone, sotalol, and ibutilide. All of these agents are negatively inotropic and should be used with caution in the presence of significant left ventricular dysfunction. In patients who exhibit hypotension, severe HF, or organ hypoperfusion attributable to atrial fibrillation, immediate direct current (DC) cardioversion is the treatment of choice (10). Patients should be sedated before cardioversion is attempted, and an initial energy level of 200 J is appropriate (10). Patients with persistent or chronic atrial fibrillation should receive longterm antithrombotic therapy (146). Warfarin remains the preferred agent in this setting, but aspirin is an acceptable, albeit less effective alternative in patients with major contraindications to warfarin (146). The treatment of peri-infarctional ventricular tachyarrhythmias is similar in older and younger patients and will not be reviewed here. In general, initial therapy should follow the Advanced Cardiac Life Support (ACLS) guidelines (147), and subsequent therapy should be individualized on the basis of symptoms, severity of arrhythmia, and other factors, such as left ventricular function. Similarly, the treatment of bradyarrhythmias and conduction disturbances does not differ in younger and older patients. In general, temporary pacing (transthoracic or transvenous) should be considered in patients with symptomatic or hemodynamically compromising bradyarrhythmias unresponsive to atropine, in patients with new bundle branch block, and in patients with second- or thirddegree infranodal block complicating anterior MI. The ACLS guidelines should be followed in treating life-threatening bradyarrhythmias such as asystole (147).

Right Ventricular Infarction Right ventricular infarction occurs in up to 50% of patients with inferior MI, with somewhat higher frequency in older than in younger patients (148). The pathophysiology, clinical features, and treatment of right ventricular infarction have previously been reviewed and will not be discussed in detail here (11). However, it is worth noting that the

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presence of right ventricular infarction, as evidenced by ST-segment elevation in the right precordial electrocardiographic leads, is associated with a marked increase in hospital mortality in both younger and older patients (148,149). Myocardial Rupture Myocardial rupture is an infrequent complication of acute MI, occurring in less than 5% of patients (150–152). However, when rupture does occur, the course is frequently catastrophic, with death ensuing in over 50% to almost 100% of cases, depending on location. There are three principal types of rupture: ventricular free wall rupture, papillary muscle rupture (PMR), and ventricular septal perforation (acute VSD). PMR almost always occurs following an inferoposterior or posterolateral MI, whereas septal rupture occurs somewhat more frequently following an anterior infarct. Free wall rupture can complicate an infarct of any location. Although precise figures are unavailable, all forms of rupture appear to occur more frequently in patients over 65 years of age (151,152). Other risk factors for myocardial rupture include female gender and persistent peri-infarctional hypertension (150). Fibrinolytic therapy may also increase the risk of myocardial rupture within the first 24 to 48 hours after treatment, particularly in older patients undergoing delayed fibrinolysis (i.e., more than six hours after symptom onset) (150,152,153). Impending myocardial rupture is occasionally heralded by persistent vague chest discomfort or unexplained hypotension, but sudden hemodynamic deterioration, new or worsening heart failure, or asystolic cardiac arrest may be the first indication of the rupture (154). The presence of a new systolic murmur, particularly in association with hemodynamic deterioration, strongly suggests the possibility of papillary muscle dysfunction or ventricular septal perforation, and prompt investigation is warranted. Urgent bedside Doppler echocardiography should be performed, since this will enable accurate diagnosis in the majority of cases (155,156). Pulmonary artery catheterization can provide definitive confirmation of a septal perforation by demonstrating an oxygen saturation step up of greater than 10% at the level of the shunt (usually the right ventricle). Similarly, the presence of an abnormally elevated V-wave in the pulmonary capillary wedge pressure waveform suggests acute mitral regurgitation. Cardiac catheterization is usually necessary to define coronary anatomy in elderly patients with cardiac rupture, and left ventriculography can provide diagnostic information on the severity of mitral regurgitation and on the presence and location of an acute VSD. Once a diagnosis of acute VSD or PMR has been confirmed, supportive measures should be rapidly instituted, and urgent surgical consultation should be obtained (10). Diuretics, an IV inotropic agent, and after-load reduction with IV nitroglycerin or nitroprusside (blood pressure permitting) are appropriate therapy in most cases. Intra-aortic balloon counterpulsation is often effective in stabilizing the patient and should be strongly considered in all surgical candidates (10). Mechanical ventilation is indicated in patients with severe HF or persistent hemodynamic instability. Surgery is recommended in almost all cases of acute VSD or PMR, since medical therapy is associated with mortality rates of more than 75% (150,157). Perioperative mortality rates range from 10% to 70%, with preoperative left ventricular function and the presence of cardiogenic shock being the most important factors influencing survival (157–159). The long-term prognosis following successful surgical repair of acute VSD or PMR is favorable (157–159). Rupture of the left ventricular free wall usually progresses rapidly to pericardial tamponade, asystole, and death. Occasionally, however, the rupture will be locally

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contained as a result of pericardial adhesions or other factors, resulting in the formation of a pseudoaneurysm. Differentiation of a pseudoaneurysm from a true left ventricular aneurysm can be difficult, but echocardiography, magnetic resonance imaging, and left ventriculography are all useful in making this distinction. The hemodynamic effects of a pseudoaneurysm are variable, depending on its size and location, but there is a tendency for pseudoaneurysms to undergo further rupture, resulting in pericardial tamponade (160,161). Although conservative management may be associated with a favorable outcome in some cases (162), prompt surgical attention is usually recommended once a pseudoaneurysm has been identified (161,163). Cardiogenic Shock Cardiogenic shock is defined as the combination of markedly reduced cardiac output (cardiac index < 1.8 L/min/m2), increased left ventricular diastolic pressure or pulmonary wedge pressure (
22 mmHg), hypotension (systolic blood pressure < 80 mmHg), and tissue hypoperfusion (e.g., prerenal azotemia, impaired sensorium) (164,165). This syndrome occurs twice as frequently in elderly patients with acute MI as in younger subjects, and it accounts for most of the excess mortality associated with acute MI in the elderly (166). Moreover, despite major advances in the treatment of acute MI over the last 30 years, the case fatality rate from cardiogenic shock remains high (166–168). The causes of cardiogenic shock complicating acute MI are similar to the causes of HF and hypotension. Since few patients survive cardiogenic shock in the absence of a treatable underlying disorder, immediate evaluation for a potentially correctable problem is critical. Emergent Doppler echocardiography should be performed to assess overall left ventricular function and to rule out valvular lesions, pericardial disease, and septal perforation (10). Pulmonary artery catheterization is indicated both to facilitate diagnosis and for guiding therapy (10). Cardiac catheterization may be necessary in some cases if the diagnosis remains in doubt, or as a prelude to PCI or corrective surgery. Although emergent catheterization and coronary revascularization have been shown to improve outcomes in patients up to age 75 with cardiogenic shock complicating acute MI, patients over age 75 may not benefit from these interventions (169). In patients with a potentially reversible cause of shock, maximally aggressive therapy is indicated to stabilize the patient. In most cases, this will include assisted ventilation, an intra-aortic balloon pump (170), and IV vasoactive therapy. However, when shock is due to irreversible myocardial damage or other untreatable disorder, invasive interventions are unlikely to influence survival and should generally be avoided.

NON-ST-ELEVATION MYOCARDIAL INFARCTION Non-ST-elevation MI increases in frequency with advancing age and accounts for over 50% of all MIs in patients over the age of 70 (7,9). While ST-elevation MIs are almost always caused by total thrombotic occlusion of the infarct-related vessel (171), the pathogenesis of non-ST-elevation MI is more variable. In the elderly, non-ST-elevation MI may be precipitated by a sustained imbalance between myocardial oxygen supply and demand resulting from severe hypertension, marked hypoxemia due to heart failure or pulmonary embolus, atrial fibrillation with rapid ventricular response, or acute hypotension due to sepsis or other causes. Diffuse, multivessel coronary disease is often present, but total occlusion of the infarct artery is the exception rather than the rule (172,173).

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The short-term prognosis following non-ST-elevation MI tends to be better than that following ST-elevation MI, since non-ST-elevation MIs are usually smaller and associated with greater preservation of ventricular function (174). However, patients with non-ST-elevation MI are at increased risk for recurrent ischemia and reinfarction, and long-term survival is similar to that of patients with ST-elevation MI (174,175). In one series, over 60% of all deaths within the first year after hospitalization for acute MI occurred in patients over the age of 70 presenting with non-ST-elevation infarctions (176). As the clinical course following non-ST-elevation MI is distinct from that following ST-elevation MI, numerous studies have focused specifically on the management of this disorder. In general, the pharmacotherapy of non-ST-elevation MI should include aspirin, LMWH or unfractionated heparin, and a b-blocker (177). Clopidogrel should also be initiated in most cases, especially if PCI is anticipated (9,10,73). A glycoprotein IIb/IIIa inhibitor should also be considered in patients likely to undergo early PCI (69,70,177). Nitrates should be administered for persistent or recurrent chest pain or if heart failure is present. In the absence of ST-elevation or left bundle branch block, fibrinolytic therapy has not been shown to be efficacious and should be avoided (19). Several studies have compared early cardiac catheterization and revascularization with conventional medical therapy in patients with unstable angina or non-ST-elevation MI (178–185). Although the results of these trials have been somewhat inconsistent, on balance the data suggest that early revascularization is beneficial in high-risk patients, including the elderly (9). These findings are reflected in the most recent guidelines for management of non-ST-elevation acute coronary syndromes, which indicate that an invasive approach to therapy is warranted in appropriately selected patients (177). It should be noted, however, that in the Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the ACC/AHA Guidelines (CRUSADE) quality improvement initiative, an early invasive management strategy did not reduce hospital mortality after adjusting for relevant covariates in a cohort of 5794 patients 75 years of age or older with non-ST-elevation ACS (186). Therefore, caution is warranted in the selection of very elderly patients with non-ST-elevation MI for early catheterization and revascularization (9).

RISK STRATIFICATION In the past 25 years, the concept of risk stratification has been developed as a means for selecting subgroups of post-MI patients who are most likely to benefit from further diagnostic and therapeutic measures, and conversely, to identify those with a favorable prognosis who are unlikely to benefit from high-cost interventions (187). Factors associated with an increased risk for adverse outcomes include older age, anterior MI location, ischemia occurring either spontaneously or during a post-MI stress test, reduced left ventricular systolic function (especially an ejection fraction less than 40%), frequent premature ventricular contractions or higher grades of ventricular ectopy, reduced heart rate variability (188), increased fibrinogen (189), and elevated C-reactive protein (189,190). Although none of the major risk stratification studies have specifically targeted older patients, key factors identified in younger individuals, particularly left ventricular dysfunction and residual myocardial ischemia, almost certainly retain their prognostic significance in the elderly. In older patients who are suitable candidates for invasive treatment, further risk stratification seems appropriate, and should include an echocardiogram or radionuclide ventriculogram to assess left ventricular function, and an exercise or

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pharmacological stress test (e.g., adenosine thallium or dobutamine echocardiogram) to determine the extent of residual ischemia (191–193). On the basis of the results of these investigations, additional intervention may be appropriate, but further study is needed to define the optimal approach to managing high-risk elderly patients. ETHICAL ISSUES In general, the foregoing discussion has been predicated on the notion that a given patient is an “appropriate” or “suitable” candidate for each intervention under consideration. These terms, while vague, imply that not all patients should receive every intervention, and that multiple factors must be taken into consideration during the decision-making process. Among these are the wishes of the patient, as expressed either directly or through a prior communication such as a living will; the anticipated impact of the intervention on quality of life and long-term prognosis; the potential for the intervention itself to add to the patient’s suffering; and the concerns of the patient’s family and friends. The physician’s role in guiding these decisions is critically important, and a high level of compassion, honesty, and respect for the patient’s autonomy is required. Thus, the physician must provide a balanced view of the available therapeutic options, including a realistic appraisal of the likelihood of various outcomes and adverse events. The physician should avoid creating an overly grim picture, but at the same time must avoid fostering unrealistic hopes. Finally, when the patient’s condition is such that death seems inevitable, the physician must be able to provide appropriate counsel to forego or withdraw interventions that are unlikely to be helpful, and which will only serve to prolong the dying process. In addition, the physician must provide comfort and emotional support for the patient and family. In this regard, the importance of the nursing staff, members of the clergy, and other health professionals in helping the patient and family deal with emotional issues and other concerns cannot be overemphasized. SUMMARY Acute myocardial infarction occurs at increasing frequency with advancing age, and older patients with acute MI are at increased risk for major complications, including HF, arrhythmias and conduction disturbances, myocardial rupture, cardiogenic shock, and death. Older patients thus comprise a large high-risk subgroup of the MI population who may derive substantial benefits from appropriately selected therapeutic interventions. At the same time, many interventions are associated with increased risk in the elderly, so that individualization of treatment is essential. Optimal therapy is thus based on a careful risk– benefit assessment of the available treatment options in conjunction with appropriate consideration of patient preferences and other relevant factors. Although many therapeutic trials in acute MI patients have either excluded elderly patients or enrolled too few older subjects to permit definitive conclusions, sufficient data are available to make specific recommendations in several areas. As shown in Table 4, aspirin, LMWH, fibrinolytic agents, and primary PCI are of proven value during the acute phase of MI in selected elderly patients. Early initiation of b-blockers, ACE inhibitors, and statins is also likely to be beneficial. Following MI, aspirin, b-blockers, ACE inhibitors, and statins are of proven benefit and should be considered standard therapy in most patients. Selected patients may also benefit from clopidogrel, warfarin, percutaneous or surgical revascularization, or implantation of an ICD. Conversely, routine use of calcium channel blockers and antiarrhythmic agents is not recommended.

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Table 4 Efficacy of Selected Treatments for Acute Myocardial Infarction in Elderly Patients Effective Acute phase Aspirin LMWHa Fibrinolysisa Primary PCIa

Chronic phase Aspirin b-Blockers ACE inhibitors Statins

Probably effective

Uncertain efficacy

Ineffective

Intravenous heparina b-Blockersa ACE inhibitorsa Glycoprotein IIb/IIIa inhibitorsa Statins

Nitrates

Calcium antagonists

Clopidogrela Warfarina PCIa Coronary surgerya ICDsa

Antiarrhythmic agents Magnesium

Antiarrhythmic agents Calcium channel blockers

a

Selected subgroups; see text. Abbreviations: ACE, angiotensin-converting enzyme; ICDs, implantable cardioverter-defibrillators; LMWH, low-molecular-weight heparin; PCI, percutaneous coronary intervention.

As the age of the population continues to increase, the number of older patients at risk for acute MI will rise commensurately. Although progressively more sophisticated interventions may result in sizable reductions in post-MI morbidity and mortality, it is apparent, given the high risk of adverse outcomes in the elderly population, that the best treatment is prevention. Thus, the greatest potential for the future, as well as the greatest challenge, will be to develop more effective strategies for preventing atherosclerosis and for conquering the epidemic of coronary heart disease in our aging population. REFERENCES 1. Kozak LJ, DeFrances CJ, Hall MJ. National Hospital Discharge Survey: 2004 annual summary with detailed diagnosis and procedure data. National Center for Health Statistics. Vital Health Stat 13 2006; 162:1–209. 2. Rosamond W, Flegal K, Friday G, et al. Heart disease and stroke statistics – 2007 update. Circulation 2007; 115:e69–e171. 3. Mehta RH, Rathore SS, Radford MJ, et al. Acute myocardial infarction in the elderly: differences by age. J Am Coll Cardiol 2001; 38:736–741. 4. Roger VL, Jacobsen SJ, Weston SA, et al. Trends in the incidence and survival of patients hospitalized with myocardial infarction, Olmsted County, Minnesota, 1979 to 1994. Ann Intern Med 2002; 136:341–348. 5. Wu AH, Parsons L, Every NR, et al. Hospital outcomes in patients presenting with congestive heart failure complicating acute myocardial infarction: a report from the Second National Registry of Myocardial Infarction (NRMI-2). J Am Coll Cardiol 2002; 40:1389–1394. 6. Alexander KP, Roe MT, Chen AY, et al. Evolution in cardiovascular care for elderly patients with non-ST-segment elevation acute coronary syndromes: results from the CRUSADE National Quality Improvement Initiative. J Am Coll Cardiol 2005; 46:1479–1487. 7. Rich MW, Bosner MS, Chung MK, et al. Is age an independent predictor of early and late mortality in patients with acute myocardial infarction? Am J Med 1992; 92:7–13. 8. White HD, Aylward PE, Huang Z, et al. Mortality and morbidity remain high despite captopril and/or valsartan therapy in elderly patients with left ventricular systolic dysfunction, heart failure, or both after acute myocardial infarction: results from the Valsartan in Acute Myocardial Infarction Trial (VALIANT). Circulation 2005; 112:3391–3399.

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183. Bach RG, Cannon CP, Weintraub WS, et al. The effect of routine, early invasive management on outcome for elderly patients with non-ST-segment elevation acute coronary syndromes. Ann Intern Med 2004; 141:186–195. 184. deWinter RJ, Windhausen F, Cornel JH, et al. Early invasive versus selectively invasive management for acute coronary syndromes. N Engl J Med 2005; 353:1095–1104. 185. Mehta SR, Cannon CP, Fox KA, et al. Routine vs. selective invasive strategies in aptients with acute coronary syndromes: a collaborative meta-analysis of randomized trials. JAMA 2005; 293:2908–2917. 186. Bhatt DL, Roe MT, Peterson ED, et al. Utilization of early invasive management strategies for high-risk patients with non-ST-segment elevation acute coronary syndromes: results from the CRUSADE Quality Improvement Initiative. JAMA 2004; 292:2096–2104. 187. Krone RJ. The role of risk stratification in the early management of a myocardial infarction. Ann Intern Med 1992; 116:223–237. 188. Kleiger RE, Miller JP, Bigger JT, et al. Decreased heart rate variability and its association with increased mortality after acute myocardial infarction. Am J Cardiol 1987; 59:256–262. 189. Toss H, Lindahl B, Siegbahn A, et al. Prognostic influence of increased fibrinogen and C-reactive protein levels in unstable coronary artery disease. Circulation 1997; 96:4204–4210. 190. Tommasi S, Carluccio E, Bentivoglio M, et al. C-reactive protein as a marker for cardiac ischemic events in the year after a first, uncomplicated myocardial infarction. Am J Cardiol 1999; 83:1595–1599. 191. Ciaroni S, Delonca J, Righetti A. Early exercise testing after acute myocardial infarction in the elderly: clinical evaluation and prognostic significance. Am Heart J 1993; 126:304–311. 192. Jain S, Baird JB, Fischer KC, et al. Prognostic value of dipyridamole thallium imaging after acute myocardial infarction in older patients. J Am Geriatr Soc 1999; 47:295–301. 193. de la Torre MM, San Roman JA, Bermejo J, et al. Prognostic power of dobutamine echocardiography after uncomplicated acute myocardial infarction in the elderly. Chest 2001; 120:1200–1205.

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Management of the Older Patient After Myocardial Infarction Wilbert S. Aronow Divisions of Cardiology, Geriatrics, and Pulmonary/Critical Care, Department of Medicine, New York Medical College, Valhalla, New York, U.S.A.

INTRODUCTION Coronary artery disease (CAD) is the leading cause of death in older persons. Although persons older than 65 years comprise 12% of the population (1), approximately 60% of hospital admissions for acute myocardial infarction (MI) occur in persons older than 65 years of age, and persons older than 75 years of age account for nearly half of these admissions of patients with MI older than 65 years (2). Not only is the in-hospital mortality higher in older patients with MI than in younger patients with MI, but the postdischarge mortality rate is also higher in older persons, with the one-year cardiac mortality rate of 12% in patients aged 65 to 75 years and 17.6% in patients older than 75 years (3). Approximately two-thirds of these one-year deaths were sudden or related to a new MI (3). This chapter discusses the management of the older patient after MI. CONTROL OF CORONARY RISK FACTORS Cigarette Smoking The Chicago Stroke Study demonstrated that current cigarette smokers 65 to 74 years of age had a 52% higher mortality from CAD than nonsmokers, ex-smokers, and pipe and cigar smokers (4). Ex-smokers who had stopped smoking for one to five years had a similar mortality from CAD, as did nonsmokers (4). The Systolic Hypertension in the Elderly Program pilot project showed that smoking was a predictor of first cardiovascular event and MI/sudden death (5). At 30-year follow-up of persons 65 years of age and older in the Framingham Study, cigarette smoking was not associated with the incidence of CAD in older men and women but was associated with mortality from CAD in them (6). At 12-year follow-up of men aged 65 to 74 years in the Honolulu Heart Program, cigarette smoking was an independent risk factor for nonfatal MI and fatal CAD (7). The absolute excess risk associated with cigarette smoking was 1.9 times higher in older men than in middle-aged men. At five-year follow-up in three communities of 7178 persons 65 years of age or older, current cigarette smokers had a higher incidence of cardiovascular 327

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Table 1 Risk Factors for New Coronary Events in 664 Older Men and in 1488 Older Women Relative risk of new coronary events Risk factor

Men

Women

Age Prior coronary artery disease Cigarette smoking Hypertension Diabetes mellitus Obesity Serum total cholesterol Serum HDL cholesterol Serum triglycerides

1.04 1.7 2.2 2.0 1.9 NS 1.12a 1.70b NS

1.03 1.9 2.0 1.6 1.8 NS 1.12a 1.95c 1.002

a

1.12 times higher probability of developing new coronary events for an increment of 10 mg/dL of serum total cholesterol. b 1.70 times higher probability of developing new coronary events for a decrement of 10 mg/dL of serum HDL cholesterol. c 1.95 times higher probability of developing new coronary events for a decrement of 10 mg/dL of serum HDL cholesterol. Abbreviations: NS, not significant by multivariate analysis; HDL, high-density lipoprotein. Source: From Ref. 10.

mortality than nonsmokers (relative risk ¼ 2 for men and 1.6 for women) (8). The incidence of cardiovascular death in former smokers was similar to those who had never smoked (8). At six-year follow-up of older men and women in the Coronary Artery Surgery Study registry, the relative risk of MI or death was 1.5 for persons aged 65 to 69 years and 2.9 for persons 70 years or older who continued smoking compared with quitters during the year before study enrollment (9). At 40-month follow-up of 664 men of mean age 80 years, and at 48-month followup of 1488 women of mean age 82 years, current cigarette smoking increased the relative risk of new coronary events (nonfatal or fatal MI or sudden cardiac death) 2.2 times in older men and 2.0 times in older women (Table 1) (10). We have also observed that cigarette smoking aggravates angina pectoris and precipitates silent myocardial ischemia in older persons with CAD. On the basis of the available data, older persons who smoke should be strongly encouraged to stop smoking because it will reduce cardiovascular mortality and all-cause mortality after MI. A smoking cessation program should be recommended. Hypertension Increased peripheral vascular resistance is the cause of systolic and diastolic hypertension in older persons. Systolic hypertension in older persons is diagnosed if the systolic blood pressure is 140 mmHg or higher on three occasions (11,12). Diastolic hypertension in older persons is diagnosed if the diastolic blood pressure is 90 mmHg or higher on three occasions (1,12). Isolated systolic hypertension in older persons is diagnosed if the systolic blood pressure is 140 mmHg or higher on three occasions, and the diastolic blood pressure is normal (11,12). In a study, isolated systolic hypertension was observed in 51% of 499 older persons with hypertension (12). Isolated systolic hypertension and diastolic hypertension are both associated with increased cardiovascular morbidity and mortality in older persons (13). Increased systolic blood pressure is a greater risk factor for cardiovascular morbidity and mortality than

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Table 2 Decrease in New Coronary Events in Older Persons with Hypertension Treated with Antihypertensive Drugs Versus Placebo Study (Ref.)

Follow-up

Result

European Working Party on High Blood Pressure in the Elderly (14) (age 60–97 yr) Swedish Trial in Old Patients With Hypertension (15) (age 70–84 yr)

4.7 yr

Medical Research Council (16) (age 65–74 yr) Systolic Hypertension in the Elderly Program (17) (mean age 72 yr) Systolic Hypertension in Europe (18) (mean age 70 yr)

5.8 yr

Drug therapy caused a 60% reduction in fatal MIs and a 47% reduction in cardiac deaths Drug therapy caused a 25% decrease in fatal MIs and a 67% decrease in sudden deaths. Drug therapy caused a 19% reduction in coronary events. Drug therapy caused a 27% decrease in nonfatal MIs plus coronary deaths. Drug therapy caused a 26% reduction in fatal and nonfatal cardiac events.

25 mo

4.5 yr

2.0 yr

Abbreviation: MIs, myocardial infarctions.

increased diastolic blood pressure (13). The higher the systolic or diastolic blood pressure, the greater the morbidity and mortality from CAD in older men and women. At 30-year follow-up of persons aged 65 years and older in the Framingham Study, systolic hypertension correlated with the incidence of CAD in older men and women (6). Diastolic hypertension correlated with CAD in older men but not in older women (6). At 40-month follow-up of older men and 48-month follow-up of older women, systolic or diastolic hypertension increased the relative risk of new coronary events 2.0 times in men and 1.6 times in women (Table 1) (10). Older persons with hypertension should be treated initially with salt restriction, weight reduction if necessary, cessation of drugs that increase blood pressure, avoidance of alcohol and tobacco, increase in physical activity, reduction of dietary saturated fat and cholesterol, and maintenance of adequate dietary potassium, calcium, and magnesium intake. Antihypertensive drugs have been demonstrated to decrease new coronary events in older men and women with hypertension (Table 2) (14–18). The Joint National Committee (JNC) on Detection, Evaluation, and Treatment of High Blood Pressure recommends as initial drug therapy diuretics or b blockers because these drugs have been shown to reduce cardiovascular morbidity and mortality in controlled clinical trials (11). Persons with prior MI should be treated with b blockers and angiotensin-converting enzyme (ACE) inhibitors and not treated with calcium channel blockers or a blockers (11,19–26). JNC VII also recommends use of aldosterone antagonists in the treatment of hypertension after MI on the basis of the EPHESUS trial (11,27). Patients treated with aldosterone antagonists should not have significant renal dysfunction or hyperkalemia (19). In an observational prospective study 1212 men and women, mean age 80 years, with prior MI and hypertension were treated with b blockers, ACE inhibitors, diuretics, calcium channel blockers, or a blockers; at 40-month follow-up, the incidence of new coronary events in persons treated with one antihypertensive drug was lowest in persons treated with b blockers or ACE inhibitors (26). In older persons treated with two antihypertensive drugs, the incidence of new coronary events was lowest in persons treated with b blockers plus ACE inhibitors (26). The benefit of b blockers in reducing coronary events in older persons with prior MI is especially increased in persons with diabetes mellitus (22), symptomatic peripheral

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arterial disease (23), abnormal left ventricular ejection fraction (LVEF) (21,28), complex ventricular arrhythmias with abnormal LVEF (29) or normal LVEF (30), and with congestive heart failure (CHF) with abnormal LVEF (31) or normal LVEF (32). b Blockers should also be used to treat older persons with hypertension who have angina pectoris (33), myocardial ischemia (34), supraventricular tachyarrhythmias such as atrial fibrillation with a rapid ventricular rate (35), hyperthyroidism (36), preoperative hypertension (11), migraine (11), or essential tremor (11). In addition to b blockers, older persons with hypertension and CHF should be treated with diuretics and ACE inhibitors or angiotensin receptor blockers (ARBs) and patients with persistent severe symptoms with aldosterone antagonists (11,27,37,38). ACE inhibitors or ARBs should also be administered to persons with diabetes mellitus, renal insufficiency, or proteinuria (11,39). The blood pressure should be lowered to less than 140/90 mmHg after MI, to less than 130/80 mmHg in persons with diabetes mellitus or renal insufficiency, and preferably to less than 120/80 mmHg (11,19). Dyslipidemia Serum Total Cholesterol In the Framingham Study, serum total cholesterol was an independent risk factor for CAD in older men and women (40). Among patients aged 65 years or older with prior MI in the Framingham Study, serum total cholesterol was most strongly related to death from CAD and to all-cause mortality (41). Many other studies have documented that a high serum total cholesterol is a risk factor for new coronary events in older men and women (5,10,42–44). During nine-year follow-up of 350 men and women, mean age 79 years, in the Bronx Aging Study, a consistently increased serum low-density lipoprotein (LDL) cholesterol was associated with the development of MI in older women (45). In the Established Populations for Epidemiologic Studies of the Elderly (EPESE) project, serum total cholesterol was a risk factor for mortality from CAD in older women but not in older men (46). At 40-month follow-up of older men and 48-month follow-up of older women, an increment of 10 mg/dL of serum total cholesterol increased the relative risk of new coronary events by 1.12 times in both men and women (Table 1) (10). Serum High-Density Lipoprotein Cholesterol A low serum high-density lipoprotein (HDL) cholesterol is a risk factor for new coronary events in older men and women (5,10,40,45–48). In the Framingham Study (40), EPESE (46), and in our study (10), a low serum HDL cholesterol was a more powerful predictor of new coronary events than was serum total cholesterol. During nine-year follow-up of 350 men and women in the Bronx Aging Study, a consistently low serum HDL cholesterol level was independently associated with the development of MI, cardiovascular disease, or death in men (45). At 40-month follow-up of 664 older men and 48-month follow-up of 1488 older women, multivariate analysis showed that there was a 1.70 times higher probability of developing new coronary events in men and a 1.95 times higher probability of developing new coronary events in women for a decrement of 10 mg/dL of serum HDL cholesterol (Table 1) (10). Serum Triglycerides Hypertriglyceridemia has been reported to be a risk factor for new coronary events in older women but not in older men (10,40). At 40-month follow-up of older men and at

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48-month follow-up of older women, multivariate analysis demonstrated that serum triglycerides was not a risk factor for new coronary events in older men and was a very weak risk factor for new coronary events in older women (Table 1) (10). Drug Therapy of Hypercholesterolemia At 5.4-year median follow-up of 4444 men and women (1021 aged 65–70 years) with CAD and hypercholesterolemia in the Scandinavian Simvastatin Survival Study, compared with placebo, simvastatin 20 to 40 mg daily significantly decreased in patients aged 65 to 70 years total mortality by 34%, CAD mortality by 43%, major coronary events by 34%, nonfatal MI by 33%, any acute CAD-related endpoint by 33%, any atherosclerosis-related endpoint by 34%, and coronary revascularization procedures by 41% (Table 3) (49). The absolute risk reduction for both all-cause mortality and CAD mortality was approximately twice as great in persons 65 to 70 years of age at study entry as in those younger than 65 years (49). Table 3 Effects of Lowering Increased Serum Total Cholesterol and Low-Density Lipoprotein Cholesterol Levels by Simvastatin and Pravastatin Vs. Placebo in Older Patients with CAD Study (Ref.)

Follow-up

Results

Scandinavian Simvastatin Survival Study (49) (4444 men and women, 1021 aged 65 to 70 yr, with CAD and hypercholesterolemia)

5.4 yr

Cholesterol and Recurrent Events Trial (50) (4159 men and women, 1283 aged 65–75 yr, with MI and serum total cholesterol <240 mg/dL but serum LDL cholesterol 115 mg/dL)

5.0 yr

Long-Term Intervention with Pravastatin in Ischaemic Disease Study (51) (9014 men and women, 3514 aged 65–75 yr, with MI or unstable angina and mean serum total cholesterol 218 mg/dL).

6.1 yr

Heart Protection Study (52) (20,536 men and women, 10,697 aged 65–85 yr, with CAD, occlusive arterial disease of noncoronary arteries, diabetes, or treated hypertension and no serum lipid requirement)

5.0 yr

In patients 65 yr, compared with placebo, simvastatin decreased all-cause mortality by 34%, CAD mortality by 43%, major coronary events by 34%, nonfatal MI by 33%, any acute CAD-related event by 33%, any atherosclerosis-related endpoint by 34%, and coronary revascularization procedures by 41%. Compared with placebo, pravastatin decreased CAD death by 45%, CAD death or nonfatal MI by 39%, major coronary events by 32%, coronary revascularization by 32%, stroke by 40%, and insignificantly decreased unstable angina by 8%, and congestive heart failure by 23%. Compared with placebo, pravastatin reduced all-cause mortality by 22%, death from CAD by 24%, fatal and nonfatal MI by 29%, death from cardiovascular disease by 25%, need for coronary artery surgery by 22%, need for coronary angioplasty by 19%, hospitalization for unstable angina by 12%, and stroke by 19%. Compared with placebo, simvastatin reduced all-cause mortality by 13%, any vascular mortality by 17%, major coronary events by 27%, any stroke by 25%, any revascularization procedure by 24%, and any major vascular event by 24%.

Abbreviations: CAD, coronary artery disease; MI, myocardial infarction; LDL, low-density lipoprotein

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At five-year follow-up of 4159 men and women (1283 aged 65–75 years) with MI and serum total cholesterol levels below 240 mg/dL but serum LDL cholesterol levels greater than or equal to 115 mg/dL in the Cholesterol and Recurrent Events trial, compared with placebo, administration of pravastatin 40 mg daily significantly reduced in patients aged 65 to 75 years CAD death by 45%, CAD death or nonfatal MI by 39%, major coronary events by 32%, coronary revascularization by 32%, and insignificantly reduced unstable angina pectoris by 8% and CHF by 23% (Table 3) (50). For every 1000 patients 65 years and older treated for five years with pravastatin, 225 cardiovascular hospitalizations would be prevented compared with the prevention of 121 cardiovascular hospitalizations in 1000 patients younger than 65 years (50). At 6.1-year mean follow-up of 9014 men and women (3514 of whom were aged 65–75) with MI (64%) or unstable angina pectoris (36%) and serum total cholesterol levels of 155 to 271 mg/dL in the Long-Term Intervention with Pravastatin in Ischaemic Disease Study, compared with placebo, pravastatin 40 mg daily significantly reduced allcause mortality by 22%, death from CAD by 24%, fatal and nonfatal MI by 29%, death from cardiovascular disease by 25%, need for coronary artery bypass surgery by 22%, need for coronary angioplasty by 19%, hospitalization for unstable angina pectoris by 12%, and stroke by 19% (Table 3) (51). The absolute benefits of treatment with pravastatin were greater in groups of persons at higher absolute risk for a major coronary event such as older persons, those with a higher serum LDL cholesterol level, those with a lower serum HDL cholesterol level, and those with a history of diabetes mellitus or smoking (51). At five-year follow-up of 20,536 British men and women (10,697 of whom were aged 65–80 years) with either CAD, occlusive arterial disease of noncoronary arteries, diabetes mellitus, or treated hypertension and no serum lipid requirement in the Heart Protection Study, compared with placebo, simvastatin 40 mg daily significantly reduced all-cause mortality by 13%, any vascular mortality by 17%, major coronary events by 27%, any stroke by 25%, any revascularization procedure by 24%, and any major vascular event by 24% (Table 3) (52). In the 1263 persons aged 75 to 80 years at study entry and 80 to 85 years at follow-up, any major vascular event was significantly reduced 28% by simvastatin. Lowering serum LDL cholesterol from less than116 mg/dL to less than 77 mg/dL by simvastatin caused a 25% significant reduction in vascular events (52). In the Heart Protection Study, 3500 persons had initial serum LDL cholesterol levels less than 100 mg/dL (52). Decrease of serum LDL cholesterol from 97 mg/dL to 65 mg/dL by simvastatin in these persons caused a similar decrease in risk as did treating patients with higher serum LDL cholesterol levels. The Heart Protection Study investigators recommended treating persons at high risk for cardiovascular events with statins, regardless of the initial levels of serum lipids, age, or gender (52). On the basis of these and other data (53–56) the American College of Cardiology/ American Heart Association (ACC/AHA) guidelines (19) and the updated National Cholesterol Education Program III guidelines (57) state that in very high-risk persons, a serum LDL cholesterol level of less than70 mg/dL is a reasonable clinical strategy. When a high-risk person has hypertriglyceridemia or low HDL cholesterol, consideration can be given to combining a fibrate or nicotinic acid with an LDL-cholesterol-lowering drug. (19,57). Diabetes Mellitus Diabetes mellitus is a risk factor for new coronary events in older men and women (10,58). At 40-month follow-up of older men and 48-month follow-up of older women, diabetes mellitus was found by multivariate analysis to increase the relative risk of new coronary events 1.9 times in men and 1.8 times in women (Table 1) (10).

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Diabetic patients are more often obese and have higher serum LDL cholesterol and triglycerides levels and lower serum HDL cholesterol levels than do nondiabetics. Diabetics also have a higher prevalence of hypertension and left ventricular hypertrophy than do nondiabetics. These risk factors contribute to the higher incidence of new coronary events in diabetics than in nondiabetics. Diabetics with microalbuminuria have more severe angiographic CAD than diabetics without microalbuminuria (59). Diabetics also have a significant increasing trend of hemoglobin A1c levels over the increasing number of vessels with CAD (60). Older diabetics after MI should be treated with dietary therapy, weight reduction therapy if necessary, and appropriate drugs if needed to control hyperglycemia. Other coronary risk factors such as smoking, hypertension, dyslipidemia, obesity, and physical inactivity should be controlled. The blood pressure should be lowered to less than 130/80 mmHg by an ACE inhibitor or by an ARB (11,19,20,39,61). The serum LDL cholesterol level should be reduced to less than 70 mg/dL (19,57). As data showed an increased incidence of coronary events and of mortality in diabetics with CAD treated with sulfonylureas (62–64), these drugs should be avoided if possible in postinfarction patients with diabetes mellitus. The hemoglobin A1c level should be reduced to less than 7% in patients with diabetes mellitus (19). Obesity In the Framingham Study, obesity was an independent risk factor for new coronary events in older men and women (58). Disproportionate distribution of fat to the abdomen assessed by the waist-to-hip circumference ratio has also found to be a risk factor for cardiovascular disease, mortality from CAD, and total mortality in older men and women (65,66). At 40-month follow-up of older men and 48-month follow-up of older women, obesity was a risk factor for new coronary events in men and women by univariate analysis but not by multivariate analysis (Table 1) (10). Obese patients who have had a MI must undergo weight reduction (19). Weight reduction is also the first approach to controlling hyperglycemia, mild hypertension, and dyslipidemia before placing persons on long-term drug therapy. Regular aerobic exercise should be advised with proper diet in treating obesity. The body mass index should be reduced to a level between 18.5 and 24.9 kg/m2 (19). Physical Inactivity Physical inactivity is associated with obesity, dyslipidemia, hyperglycemia, and hypertension. At 12-year follow-up in the Honolulu Heart Program, physically active men aged 65 years or older had a relative risk of 0.43 for CAD compared with inactive men (67). Exercise training programs are not only beneficial in preventing CAD (68) but have also been shown to improve endurance and functional capacity in older persons after MI (69,70). The goal to be achieved is at least 30 minutes of exercise daily for seven days per week with a minimum of five days of physical exercise per week (19). ASPIRIN Aspirin decreases the aggregation of platelets exposed to thrombogenic stimuli by inhibiting the cyclooxygenase enzyme reaction within the platelet and, thereby, blocking synthesis of thromboxane A2, a powerful stimulus to platelet aggregation and vasoconstriction (71).

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Randomized trials involving 20,006 patients showed that aspirin and other antiplatelet drugs administered to patients after MI decreased the incidence of recurrent MI, stroke, or vascular death by 36 events per 1000 patients treated for two years (72). The benefit of aspirin in decreasing MI, stroke, or vascular death in patients after MI was irrespective of age, sex, blood pressure, and diabetes mellitus (72). Data from the Multicenter Study of Myocardial Ischemia in 936 patients enrolled one to six months after an acute MI (70% of patients) or unstable angina pectoris (30% of patients) showed at 23-month follow-up that the cardiac mortality rate was 1.6% for aspirin users and 5.4% for nonusers of aspirin (73). Cardiac mortality was reduced by 90% in aspirin users who underwent thrombolytic therapy compared with nonusers of aspirin who underwent thrombolytic therapy (73). The Coumadin Aspirin Reinfarction Study (CARS) randomized 8803 low-risk patients after MI to aspirin 160 mg daily, aspirin 80 mg plus warfarin 1 mg daily, or to aspirin 80 mg plus warfarin 3 mg daily (74). At follow-up, the combined incidence of cardiovascular death, recurrent MI, and stroke was similar in all the three treatment groups (74). The incidence of mortality was also similar in these three treatment groups. However, the incidence of nonfatal stroke was reduced by aspirin 160 mg daily (74). Data from the Combination Hemotherapy and Mortality and Prevention Study showed in 5059 postinfarction patients that warfarin administered in a dose to achieve an international normalized ratio (INR) of 1.8 combined with low-dose aspirin did not provide a clinical benefit beyond that achieved with aspirin alone (75). Of 5490 survivors of acute MI aged 65 years or older, with no contraindications to aspirin, 4149 patients (76%) received aspirin at the time of hospital discharge (76). At the sixmonth follow-up evaluation, aspirin users had a significant 23% reduction in mortality (76). In an observational prospective study of 1410 patients, mean age 81 years, with prior MI and a serum LDL cholesterol of 125 mg/dL or higher, 832 patients (59%) were treated with aspirin (77). At three-year follow-up, use of aspirin caused a 52% significant independent reduction in new coronary events (95% CI, 0.41–0.55) (77). Use of statins caused a 54% significant independent reduction in the incidence of new coronary events (95% CI, 0.40–0.53) (77). On the basis of the available data, all patients should receive aspirin in a dose of 160 to 325 mg daily on day 1 of an acute MI and continue aspirin in a dose of 75 to 162 mg daily for an indefinite period unless there is a specific contraindication to its use (19,78). Clopidogrel is also an excellent antiplatelet drug that is effective in reducing MI, ischemic stroke, and vascular death in postinfarction patients (79). The ACC/AHA guidelines recommend the use of clopidogrel in postinfarction patients who cannot tolerate aspirin for an indefinite period unless there is a specific contraindication to its use (19,78). ANTICOAGULANTS The routine use of warfarin after MI is controversial (80). However, three well-controlled studies have shown a reduction in mortality and/or morbidity in patients receiving longterm oral anticoagulation therapy after MI (81–83). The Sixty Plus Reinfarction Study Group reported at two-year follow-up after MI of patients, mean age 68 years, that compared with placebo, acenocoumarin or phenprocoumon caused a 26% nonsignificant decrease in mortality, a 55% significant reduction in recurrent MI, and a 40% nonsignificant decrease in stroke (81). The Warfarin Reinfarction Study Group showed at 37-month follow-up after MI of patients 75 years of age or younger that compared with

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placebo, warfarin caused significant reductions in mortality (24%), recurrent MI (34%), and stroke (55%) (82). The Anticoagulation in the Secondary Prevention of Events in Coronary Thrombosis Research Group reported at 37-month follow-up after MI of patients, mean age 61 years, that compared with placebo, nicoumalone or phenprocoumon caused a 10% nonsignificant decrease in mortality, a 53% significant reduction in recurrent MI, and a 42% significant decrease in stroke (83). The ACC/AHA guidelines recommend as class I indications for long-term oral anticoagulant therapy after MI (i) secondary prevention of MI in post-MI patients unable to tolerate daily aspirin or clopidogrel, (ii) in post-MI patients with persistent atrial fibrillation, and (iii) post-MI patients with left ventricular thrombus (19,78). Long-term warfarin should be administered in a dose to achieve an INR between 2 and 3 (19,78). b BLOCKERS b Blockers are very effective antianginal and anti-ischemic agents and should be administered to all patients with angina pectoris or silent myocardial ischemia due to CAD unless there are specific contraindications to their use (33). Teo et al. (84) analyzed 55 randomized controlled trials comprising 53,268 patients that investigated the use of b blockers after MI. b Blockers significantly decreased mortality by 19% in these studies (84). A randomized, double-blind, placebo-controlled study of propranolol in high-risk survivors of acute MI at 12 Norwegian hospitals showed a 52% reduction in sudden cardiac death in persons treated with propranolol for one year (85). Table 4 shows that metoprolol (86), timolol (87,88), and propranolol (89) caused a greater decrease in mortality after MI in older persons than in younger persons. The reduction in mortality after MI in patients treated with b blockers was due to both a reduction in sudden cardiac death and recurrent MI (87–89). In persons with an LVEF less than or equal to 40% after MI, compared with placebo, persons aged 25 to 90 years randomized to carvedilol had a 23% significant reduction in mortality at 1.3-year followup (90). A retrospective cohort study also showed that MI patients aged 60 to 89 years treated with metoprolol had an age-adjusted mortality decrease of 76% (91). In the Beta Blocker Heart Attack Trial, propranolol caused a 27% decrease in mortality in patients with a history of CHF and a 25% decrease in mortality in patients without CHF (92). In this study, propranolol caused a 47% reduction in sudden cardiac death in patients with a history of CHF and a 13% reduction in sudden cardiac death in patients without CHF (92). In the Beta-Blocker Pooling Project, results from nine studies involving 3519 patients with CHF at the time of acute MI demonstrated that b blockers caused a 25% decrease in mortality (93). In the Multicenter Diltiazem Postinfarction Trial, the 2.5-year risk of total mortality in patients with an LVEF, less than 30% was 24% for patients receiving b blockers (relative risk ¼ 0.53) versus 45% for patients not receiving b blockers (94). b Blockers have also been found to reduce mortality in patients with CAD and CHF associated with an LVEF less than or equal to 35% (31,95–97) or greater than or equal to 40% (32,97). An observational prospective study was performed in 477 patients, mean age 79 years, with prior MI and an LVEF less than 40% (mean LVEF 31%) (21). At 34-month follow-up, patients treated with b blockers without ACE inhibitors had a 25% significant reduction in new coronary events and a 41% significant reduction in CHF (21). At 41-month follow-up, patients treated with both b blockers and ACE inhibitors had a significant 37% reduction in new coronary events and a significant 60% reduction in CHF (21).

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Table 4 Effect of b Blockers on Mortality After Myocardial Infarction Study (Ref.)

Follow-up

Results

Goteborg Trial (86)

90 days

Norwegian Multicenter Study (87)

17 mo (up to 33 mo)

Norwegian Multicenter Study (87)

61 mo (up to 72 mo)

Beta Blocker Heart Attack Trial (89)

25 mo (up to 36 mo)

CAPRICORN Trial (90)

1.3 yr

Compared with placebo, metoprolol caused a 21% nonsignificant decrease in mortality in patients <65 yr and a 45% significant decrease in mortality in patients 65–74 yr. Compared with placebo, timolol caused a 31% significant reduction in mortality in persons <65 yr and a 43% significant reduction in mortality in persons 65–74 yr. Compared to placebo, timolol caused a 13% nonsignificant decrease in mortality in persons <65 yr and a 19% significant decrease in mortality in persons 65–74 yr. Compared with placebo, propranolol caused a 19% nonsignificant reduction in mortality in persons <60 yr and a 33% significant reduction in mortality in persons 60–69 yr. In patients, mean age 63 yr (range 25–90 yr) with a left ventricular ejection fraction 40% after MI, compared with placebo, carvedilol caused a 23% significant reduction in mortality.

Abbreviations: CAPRICORN, Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction; MI, myocardial infarction.

A retrospective analysis of the use of b blockers after MI in a New Jersey Medicare population from 1987 to 1992 showed that only 21% of older persons after MI without contraindications to b blockers were treated with b blockers (98). Older patients, who were treated with b blockers after MI, had a 43% decrease in two-year mortality and a 22% decrease in two-year cardiac hospital readmissions compared with older patients who were not treated with b blockers (98). Use of a calcium channel blocker instead of a b blocker after MI doubled the risk of mortality (98). b Blockers have also been demonstrated to reduce mortality in older patients with complex ventricular arrhythmias after MI and an LVEF greater than or equal to 40% (30) or less than or equal to 40% (29). The decrease in mortality in older patients with heart disease and complex ventricular arrhythmias caused by propranolol is more because of an anti-ischemic effect than to an antiarrhythmic effect (34). In these patients, propranolol also markedly decreased the circadian variation of ventricular arrhythmias (99), abolished the circadian variation of myocardial ischemia (100), and abolished the circadian variation of sudden cardiac death or fatal MI (101). A meta-analysis of trials also showed that the use of b blockers after non-Q-wave MI is likely to reduce mortality and recurrent MI by 25% (102). Therefore, older patients with Q-wave MI or non-Q-wave MI without contraindications to b blockers should be treated with b blockers for at least six years after MI. b Blockers with intrinsic sympathomimetic activity should not be used. The ACC/AHA guidelines recommend that patients without a clear contraindication to b-blocker therapy should receive b blockers within a few days of MI (if not initiated acutely) and continue them indefinitely (19,78).

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NITRATES Long-acting nitrates are effective antianginal and anti-ischemic drugs (103). These drugs should be administered along with b blockers to patients after MI who have angina pectoris. The dose of oral isosorbide dinitrate prescribed should be gradually increased to a dose of 30 to 40 mg administered thrice daily if tolerated. Isosorbide-5-mononitrate in a dose of 60 mg may also be administered once daily. To avoid nitrate tolerance, there should be a nitrate-free interval of 12 hours each day (104). b Blockers should be used to prevent angina pectoris and rebound myocardial ischemia during the nitrate-free interval. ACE INHIBITORS ACE inhibitors improve symptoms, quality of life, and exercise tolerance in patients with CHF and an abnormal LVEF (105) or a normal LVEF (106). An overview of 32 randomized trials comprising 7105 patients with CHF showed that ACE inhibitors reduced mortality by 23% and mortality or hospitalization for CHF by 35% (107). Patients who develop CHF after MI should be treated with ACE inhibitors unless there are specific contraindications to their use. Table 5 shows that ACE inhibitors reduce mortality in patients after MI (20,108– 112). In the Survival and Ventricular Enlargement Trial, asymptomatic patients with an LVEF less than or equal to 40% treated with captopril 3 to 16 days after MI had, at 42-month follow-up compared with placebo, a 19% reduction in mortality, a 21% Table 5 Effect of Angiotensin-Converting Enzyme Inhibitors on Mortality in Patients After MI Study (Ref.)

Follow-up

Results

Survival and Ventricular Enlargement Trial (108)

42 mo (up to 60 mo)

Acute Infarction Ramipril Efficacy Study (109)

15 mo

Survival of Myocardial Infarction Long-Term Evaluation Trial (110)

1 yr

Trandolapril Cardiac Evaluation Study (111)

24 to 50 mo

Heart Outcomes Prevention Evaluation Study (20)

4.5 yr (up to 6 yr)

EUROPA study (112)

4.2 yr

In patients with MI and LVEF 40%, compared with placebo, captopril reduced mortality 8% in patients aged 55 yr, 13% in patients aged 56 to 64 yr, and 25% in patients aged 65 yr. In patients with MI and clinical evidence of CHF, compared with placebo, ramipril decreased mortality 2% in patients aged <65 yr and 36% in patients aged 5 yr. In patients with anterior MI, compared with placebo, zofenopril reduced mortality or severe CHF 32% in patients aged <65 yr and 39% in patients aged 65 yr. In patients, mean age 68 yr, with LVEF 35%, compared with placebo, trandolapril reduced mortality 33% in patients with anterior MI and 14% in patients without anterior MI. In patients aged 55 yr with MI (53%), cardiovascular disease (88%), or diabetes (38%) but no CHF or abnormal LVEF, ramipril reduced MI, stroke, and cardiovascular death 22% In patients, mean age 60 yr, with prior MI, compared with placebo, perindopril significantly reduced cardiovascular death, MI, or cardiac arrest by 20%

Abbreviations: MI, myocardial infarction; LVEF, left ventricular ejection fraction; CHF, congestive heart failure.

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decrease in death from cardiovascular causes, a 37% reduction in development of severe CHF, a 22% decrease in development of CHF requiring hospitalization, and a 25% reduction in recurrent MI (108). Captopril decreased mortality independent of age, sex, blood pressure, LVEF, and use of thrombolytic therapy, aspirin, or b blockers (108). In the Heart Outcomes Prevention Evaluation Study, 9217 patients aged 55 years and older (55% aged 65 years) with MI (53%), cardiovascular disease (88%), or diabetes mellitus (38%) but no CHF or abnormal LVEF were randomized to ramipril 10 mg daily or placebo (20). At 4.5-year follow-up, compared with placebo, ramipril significantly reduced the incidence of MI, stroke, and cardiovascular death by 22% (95% CI, 0.70–0.86) (20). At 4.2-year follow-up of 13, 655 patients with prior MI and stable CAD in the EUROPA trial, compared with placebo, patients randomized to perindopril had a 20% significant reduction in cardiovascular death, recurrent MI, or cardiac arrest (112). On the basis of the available data, ACE inhibitors should be administered to all patients after MI unless there are specific contraindications to their use (19,78). ALDOSTERONE ANTAGONISTS At 16-month follow-up of 6632 patients after MI with an LVEF less than or equal to 40% and either CHF or diabetes mellitus treated with ACE inhibitors or ARBs and 75% with b blockers, compared with placebo, patients randomized to eplerenone 50 mg daily had a significant 15% reduction in mortality and a 13% significant reduction in death from cardiovascular causes or hospitalization for cardiovascular events. (113). The ACC/AHA guidelines recommend an aldosterone antagonist in patients after MI treated with ACE inhibitors plus b blockers if they have an LVEF less than or equal to 40% with either CHF or diabetes mellitus if they do not have significant renal dysfunction or hyperkalemia (19). CALCIUM CHANNEL BLOCKERS Teo et al. (84) analyzed randomized controlled trials comprising 20,342 patients that investigated the use of calcium channel blockers after MI. Mortality was insignificantly higher (relative risk ¼ 1.04) in patients treated with calcium channel blockers (84). A meta-analysis of randomized, clinical trials of the use of calcium channel blockers in patients with MI and both unstable and stable angina pectoris showed that the relative risk for mortality in the trials using dihydropyridines such as nifedipine that increase heart rate was 1.16 (114). The calcium channel blockers diltiazem and verapamil, which reduce heart rate, had no effect on survival (114). Furberg et al. (115) performed a meta-analysis of the effect of nifedipine on mortality in 16 randomized secondary prevention clinical trials in patients with CAD. In this study, the relative risk for mortality was 1.06 for patients treated with nifedipine 30 to 50 mg daily, 1.18 for patients treated with nifedipine 60 mg daily, and 2.83 for patients treated with nifedipine 80 mg daily (115). The Multicenter Diltiazem Postinfarction Trial demonstrated at 25-month follow-up in patients after MI that compared with placebo, diltiazem caused no significant effect on mortality or recurrent MI (116). However, in patients with pulmonary congestion at baseline or an LVEF less than 40%, diltiazem caused a significant increase in new cardiac events (hazard ratios ¼ 1.41 and 1.31, respectively) (116). In this study, diltiazem also increased the incidence of late-onset CHF in patients with an LVEF less than 40% (117).

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Use of a calcium channel blocker instead of a b blocker after MI in a New Jersey Medicare population also doubled the risk of mortality (98). Since no calcium channel blocker has been shown to improve survival after MI except for the subgroup of patients with normal LVEF treated with verapamil in the Danish Verapamil Infarction Trial II (118), calcium channel blockers should not be used in the treatment of patients after MI. However, if patients after MI have persistent angina pectoris despite treatment with b blockers and nitrates, a nondihydropyridine calcium channel blocker such as verapamil or diltiazem should be added to the therapeutic regimen if the LVEF is normal. If the LVEF is abnormal, amlodipine or felodipine should be added to the therapeutic regimen. The ACC/AHA guidelines state that there are no class I indications for the use of calcium channel blockers after MI (19,78). ANTIARRHYTHMIC THERAPY Class I Drugs A meta-analysis of 59 randomized controlled trials comprising 23,229 patients that investigated the use of quinidine, procainamide, disopyramide, imipramine, moricizine, lidocaine, tocainide, phenytoin, mexiletine, aprindine, encainide, and flecainide after MI demonstrated that mortality was significantly higher in patients receiving class I antiarrhythmic drugs than in patients receiving no antiarrhythmic drugs (odds ratio ¼ 1.14) (84). None of the 59 studies showed a decrease in mortality by class I antiarrhythmic drugs (84). In the Cardiac Arrhythmia Suppression Trials I and II, older age also increased the likelihood of adverse effects including death in patients after MI receiving encainide, flecainide, or moricizine (119). Compared with no antiarrhthmic drug, quinidine or procainamide did not decrease mortality in older patients with CAD, normal or abnormal LVEF, and presence versus absence of ventricular tachycardia (120). On the basis of the available data, patients after MI should not receive class I antiarrhythmic drugs. d,l-Sotalol and d-Sotalol Studies comparing the effect of d,l-sotalol with placebo on mortality in patients with complex ventricular arrhythmias have not been performed. Compared with placebo, d,l-sotalol did not reduce mortality in post-MI patients followed for one year (121). In the Survival with Oral d-Sotalol (SWORD) trial, 3121 survivors of MI with an LVEF less than or equal to 40% were randomized to d-sotalol or placebo (122). Mortality was significantly higher at 148-day follow-up in patients treated with d-sotalol (5.0%) than in patients treated with placebo (3.1%) (122). On the basis of the available data, d,l-sotalol, and d-sotalol should not be used to treat patients after MI. Amiodarone In the European Myocardial Infarction Amiodarone Trial, 1486 survivors of MI with an LVEF less than or equal to 40% were randomized to amiodarone (743 patients) or to placebo (743 patients) (123). At two-year follow-up, 103 patients treated with amiodarone and 102 patients treated with placebo had died (123). In the Canadian Amiodarone Myocardial Infarction Arrhythmia Trial, 1202 survivors of MI with nonsustained ventricular tachycardia or complex ventricular arrhythmias were randomized to amiodarone or to placebo (124). Amiodarone was very effective in suppressing ventricular tachycardia

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and complex ventricular arrhythmias. However, the mortality rate at 1.8-year follow-up was not significantly different in the patients treated with amiodarone or placebo (124). In addition, early permanent discontinuation of drug for reasons other than outcome events occurred in 36% of patients taking amiodarone (124). In the Sudden Cardiac Death in Heart Failure Trial, 2521 patients, mean age 60 years, with class II or III CHF, an LVEF of less than or equal to 35%, and a mean QRS duration on the resting ECG of 120 milliseconds, were randomized to placebo, amiodarone, or an automatic implantable cardioverter-defibrillator (AICD) (125). At 46-month median follow-up, compared with placebo, amiodarone insignificantly increased mortality by 6% (125). At 46-month median follow-up, compared with placebo, ICD therapy significantly reduced all-cause mortality by 23% (125). In the Cardiac Arrest in Seattle: Conventional Versus Amiodarone Drug Evaluation Study, the incidence of pulmonary toxicity was 10% at two years in patients receiving amiodarone in a mean dose of 158 mg daily (126). The incidence of adverse effects for amiodarone also approaches 90% after five years of therapy (127). On the basis of the available data, amiodarone should not be used in the treatment of patients after MI. b Blockers However, b blockers have been demonstrated to reduce mortality in patients with nonsustained ventricular tachycardia or complex ventricular arrhythmias after MI in patients with normal or abnormal LVEF (29,30,128,129). On the basis of the available data, b blockers should be used in the treatment of older patients after MI, especially if nonsustained ventricular tachycardia or complex ventricular arrhythmias are present, unless there are specific contraindications to their use. Automatic Implantable Cardioverter-Defibrillator In the Antiarrhythmics Versus Implantable Defibrillators (AVID) trial, 1016 patients, mean age 65 years, with a history of ventricular fibrillation or serious sustained ventricular tachycardia were randomized to an AICD or to drug therapy with amiodarone or d,l-sotalol (130). Patients treated with an AICD had a 39% reduction in mortality at one year, a 27% decrease in mortality at two years, and a 31% reduction in mortality at three years (130). If patients after MI have life-threatening ventricular tachycardia or ventricular fibrillation, an AICD should be inserted. The efficacy of the AICD implanted for ventricular fibrillation or recurrent sustained ventricular tachycardia on survival is similar in older and younger patients (131). The Multicenter Automatic Defibrillator Implantation Trial (MADIT) randomized 196 patients with prior MI, an LVEF less than or equal to 35%, a documented episode of asymptomatic nonsustained ventricular tachycardia, and inducible ventricular tachycardia or ventricular fibrillation not suppressed by intravenous procainamide, or an equivalent drug at electrophysiologic study to conventional medical therapy or implantation of an AICD (132). At 27-month follow-up, patients treated with an AICD had a 54% reduction in mortality (132). These data favor the prophylactic implantation of an AICD in post-MI patients at very high risk for sudden cardiac death. MADIT II randomized 1232 patients, mean age 64 years, with a prior MI and an LVEF of less than or equal to 30% to an AICD or to conventional medical therapy (133). At 20-month follow-up, compared with conventional medical therapy, the AICD significantly reduced all-cause mortality from 19.8% to 14.2% (hazard ratio ¼ 0.69; 95% CI, 0.51–0.93) (133). The effect of AICD therapy in improving survival was similar in

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patients stratified according to age, sex, LVEF, New York Heart Association class, and QRS interval (133). In MADIT II, the reduction in sudden cardiac death in patients treated with an AICD was significantly reduced by 68% in 574 patients aged below 65 years (p ¼ 0.02), by 65% in 455 patients aged 65 to 74 years (p ¼ 0.005), and by 68% in 204 patients aged 75 years or older (p ¼ 0.05) (134). The median survival in 348 octogenarians treated with AICD therapy was more than four years (135). These data favor considering the prophylactic implantation of an AICD in postinfarction patients with an LVEF of less than or equal to 30%.

HORMONE REPLACEMENT THERAPY The Heart Estrogen/Progestin Replacement Study (HERS) investigated in 2763 women with documented CAD the effect of hormonal replacement therapy versus double-blind placebo on coronary events (136). At 4.1-year follow-up, there were no significant differences between hormonal replacement therapy and placebo in the primary outcome (nonfatal MI or CAD death) or in any of the secondary cardiovascular outcomes. However, there was a 52% significantly higher incidence of nonfatal MI or death from CAD in the first year in patients treated with hormonal replacement therapy (relative hazard ¼ 1.52; 95% CI, 1.01–2.29) than in patients treated with placebo (136). Women on hormonal replacement therapy had a significantly higher incidence of venous thromboembolic events (relative hazard ¼ 2.89, 95% CI, 1.50–5.58) and a significantly higher incidence of gallbladder disease requiring surgery (relative hazard ¼ 1.38, 95% CI, 1.00–1.92) than women on placebo. The Estrogen Replacement and Atherosclerosis trial randomized 309 postmenopausal women, mean age 66 years, with coronary angiographic evidence of significant CAD to estrogen plus progestin, estrogen alone, or double-blind placebo (137). At 3.2-year follow-up, quantitative coronary angiography showed no between-group differences in progression of coronary atherosclerosis (137). At 6.8-year follow-up in the HERS trial, hormonal replacement therapy did not reduce the risk of cardiovascular events in women with CAD (138). The investigators concluded that hormonal replacement therapy should not be used to reduce the risk of coronary events in women with CAD (138). At 6.8-year follow-up in the HERS trial, allcause mortality was insignificantly increased 10% by hormonal replacement therapy (relative hazard ¼ 1.10; 95% CI, 0.92–1.31) (138). The overall incidence of venous thromboembolism at 6.8-year follow-up was significantly increased by 208% with hormonal replacement therapy (relative hazard ¼ 2.08; 95% CI, 1.28–3.40) (139). At 6.8-year follow-up, the overall incidence of biliary tract surgery was significantly increased by 48% (relative hazard ¼ 1.48; 95% CI, 1.12–1.95), the overall incidence for any cancer was insignificantly increased by 19% (relative hazard ¼ 1.19; 95% CI, 0.95–1.50), and the overall incidence for any fracture was insignificantly increased by 4% (relative hazard ¼ 1.04; 95% CI, 0.92–1.31) (139). The estrogen plus progestin component of the Women’s Health Initiative (WHI) study included 16,608 healthy postmenopausal women aged 50 to 79 years with an intact uterus who were randomized to estrogen plus progestin or to placebo (140). At 5.2-year follow-up, this component of the WHI study was prematurely discontinued because the excess risk of events included in the global index was 19 per 10,000 person-years (140). Absolute excess risks per 10,000 person-years included seven more coronary events, eight more strokes, eight more episodes of pulmonary embolism, and eight more invasive breast

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cancers, while absolute risk reductions per 10,000 person-years included six fewer colorectal cancers and five fewer hip fractures (140). On the basis of the available data, hormonal replacement therapy should not be used in postmenopausal women with CAD (19,78). INFLUENZA VACCINATION Evidence from cohort studies and a randomized clinical trial indicate that annual vaccination against seasonal influenza prevents cardiovascular morbidity and mortality in patients with cardiovascular disease (141). The ACC/AHA guidelines recommend influenza immunization with inactivated vaccine administered intramuscularly as part of secondary prevention in persons with CAD or other atherosclerotic vascular disease with a class I indication (141). CORONARY REVASCULARIZATION Medical therapy alone is the preferred treatment in older patients after MI. The two indications for coronary revascularization in older patients after MI are prolongation of life and relief of unacceptable symptoms despite optimal medical management. In a prospective study of 305 patients aged 75 years and older with chest pain refractory to at least two antianginal drugs, 150 patients were randomized to optimal medical therapy and 155 patients to invasive therapy (142,143). In the invasive group, 74% had coronary revascularization (54% coronary angioplasty and 20% coronary artery bypass graft surgery). During the six-month follow-up, one-third of the medically treated group needed coronary revascularization for uncontrollable symptoms. At six-month follow-up, death, nonfatal MI, or hospital admission for an acute coronary syndrome was significantly higher in the medically treated group (49%) than in the invasive group (19%) (142,143). Revascularization by percutaneous transluminal coronary angioplasty (see chap. 14) or by coronary artery bypass graft surgery (see chap. 13) is extensively discussed elsewhere. If coronary revascularization is performed, aggressive medical therapy must be continued. REFERENCES 1. Stenson WB, Sanders CA, Smith HC. Cardiovascular care of the elderly: economic considerations. J Am Coll Cardiol 1987; 10(suppl A):A18–A21. 2. Weaver WD, Litwin PE, Martin JS, et al. Effect of age on the use of thrombolytic therapy and mortality in acute myocardial infarction. J Am Coll Cardiol 1991; 18:657–662. 3. Smith SC Jr., Gilpin E, Ahnve S, et al. Outlook after acute myocardial infarction in the very elderly compared with that in patients aged 65 to 75 years. J Am Coll Cardiol 1990; 16:784–792. 4. Jajich CL, Ostfield AM, Freeman DH Jr. Smoking and coronary heart disease mortality in the elderly. JAMA 1984; 252:2831–2834. 5. Siegel D, Kuller L, Lazarus NB, et al. Predictors of cardiovascular events and mortality in the Systolic Hypertension in the Elderly Program pilot project. Am J Epidemiol 1987; 126:385–399. 6. Kannel WB, Vokonas PS. Primary risk factors for coronary heart disease in the elderly: The Framingham Study. In: Wenger NK, Furberg CD, Pitt B, eds. Coronary Heart Disease in the Elderly. New York: Elsevier Science Publishing, 1986:60–92. 7. Benfante R, Reed D, Frank J. Does cigarette smoking have an independent effect on coronary heart disease incidence in the elderly? Am J Public Health 1991; 81:897–899.

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Surgical Management of Coronary Artery Disease in the Elderly Edward A. Stemmer University of California at Irvine School of Medicine and Veterans Affairs Medical Center, Long Beach, California, U.S.A.

Wilbert S. Aronow Divisions of Cardiology, Geriatrics, and Pulmonary/Critical Care, Department of Medicine, New York Medical College, Valhalla, New York, U.S.A.

Since 1990, the U.S. population over the age of 65 years has been growing rapidly in both absolute and relative numbers. Currently, 36.8 million individuals are over 65 years of age. By 2010, when the first of the baby boomers (those born between 1946 and 1964) reach 65, there will be 40 million people aged 65 years or older. By 2030, when the last of the baby boomers reach 65, the number of individuals aged 65 years or older is projected to reach 70 million. Moreover, the elderly are living longer. In 1900, at age 65, 13% of men and 16% of women could expect to live to age 85 years. By 1992, these percentages were 30% and 50%, respectively. As the baby boomers age, the percentage of the population aged 85 years or older will grow from the current level of 1.4% to 2.4% in 2030 and to 4.6% in the year 2050. Octogenarians are, in fact, the fastest growing segment of the population in the United States (Table 1) (1,2). While arthritis is the most common chronic disease borne by the elderly, heart disease is the most common cause of major disability in the elderly as well as the most common reason for hospitalization and death. Clinically evident heart disease affects 30% of those aged 65 years or older (1,3). Approximately 12% of the elderly population suffers from major limitations of activity because of heart disease (4). Forty percent of deaths in the over-65 population are due to heart disease (5). Clinically recognized ischemic heart diseases (and its complications) are responsible for 70% of the deaths due to heart disease (6,7). In 1993, 7–8% of men and women aged 65 years or older were hospitalized for “diseases of the heart,” with an average hospital stay of six to seven days (1,8). Congestive heart failure (CHF) was the most common reason for hospitalization (9), but from 6% to 9% of the elderly discharged with a diagnosis of “diseases of the heart” had

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Table 1 Demographics of Current and Projected Resident Population of the United States: 1900–2050 Number of persons (in 1000s)

Percentage of resident population

Years

Resident population (in 1000s)


65


85


65


85

1900 1995 2010 2030 2040 2050

75995 263434 297716 346899 369980 393931

3116 33648 40104 70175 80109 77014

125 3598 5671 8455 13552 18223

4.1 12.8 13.2 20.0 20.3 20.0

0.2 1.4 1.9 2.4 3.7 4.6

Life expectancy (yr) At birth At age 65 49.2 76.3 77.9 78.8 79.3 79.8

11.9 17.7 18.6 20.0 20.7 21.6

undergone coronary arterial bypass grafting (CABG) at an estimated cost of $6 billion to $7 billion per year (8,10–15). As modern medical treatment is being employed for increasing numbers of progressively older patients, dire predictions about the solvency of Social Security and Medicare abound. By 2030, the number of individuals over the age of 65 will be more than double (2). It has been suggested that by 2050 outflow of funds from Social Security and Medicare will exceed inflow by 75% (16). Rationing (in one form or another) of health care coverage for the elderly is being discussed openly. Health care planners question whether the rapidly increasing expenditure of funds, particularly for highly technical procedures, is justified in a population that is nearing the end of life or, at least, the end of active life (17). It is against this background that the merits of performing CABG in the elderly must be discussed. Before deciding whether or not the benefits that the elderly reap from sophisticated surgical procedures are worth the risks and the costs, however, it is important to appreciate the characteristics of the population commonly referred to as elderly. How sick, impaired, and disabled are the elderly? How prevalent is coronary artery disease (CAD) in the elderly? Does the nature and presentation of CAD in the elderly differ from that in a younger population? Can current medical and surgical treatments of ischemic heart disease prevent disabilities, restore function, prolong life, and increase the quality of life in the elderly with CAD?

CHARACTERISTICS OF THE OVER-65 POPULATION Most discussions about the elderly center on prevalence of disease, degrees of physical or mental impairment, need for hospitalization or institutionalization, and end-of-life expenses. Indeed, 80% of the elderly population does suffer from one or more chronic conditions. Overall, however, the elderly population is surprisingly healthy. Only 20% of those in the 65- to 74-year-old group have major or severe limitations of activities because of their chronic diseases (Table 2) (18). Only 5% reside in institutions (many temporarily) (19). In 1994, 77% of those older than 65 years of age were living in their own houses. Of these, 55% were living with their spouses; 30% lived alone but independently; 12% lived with other relatives; only 2% resided with nonrelatives (20). Half of those aged 85 or older still live alone or with their spouses (21). In the community, about 5% of the elderly

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have some clinically detectable impairment of cognitive function but only 2% of the elderly have major limitations of activity because of mental or nervous disease (22). Seventy percent of the elderly rate their health as good, very good, or excellent (23). Whatever the nature, degree, and permanence of their disabilities might be, it is apparent that the chronic diseases that cause severe disability and death in the elderly can be treated very successfully by currently available methods (Tables 3 and 4). It is also apparent that heart disease stands out as the most common chronic disease that results in major limitations of activity and death in the elderly (4,18,24). Table 2 Percentage of Noninstitutionalized Population Whose Activities Are Limited by One or More Chronic Conditions Degree of limitation Age group (yr)

None

Minor

Major

Severe

65 or older 65 to 74 75 or older

61.2 65.6 54.7

15.6 13.6 18.6

12.5 10.4 15.7

10.6 10.4 11.1

Table 3 Percentage of Population Age 65 or Older with Major Limitations of Activities Because of Specific Conditions Major limitations (%) Disease/condition Heart Arthritis Visual impairment Emphysema Hypertension Cerebrovascular disease Mental/nervous Diabetes mellitus Other circulatory

Men

Women

12 8 4 4 3 3 2 3 3

10 13 5 – 5 3 2 3 3

Table 4 Selected Causes of Death in Patients Aged 65 and Above (1992) Men

Women

Cause

Number

Percentage of total

Number

Percentage of total

All causes Heart disease Cancer Stroke Obstructive pulmonary disease Pneumonia/influenza Diabetes mellitus Accidents

735,298 271,214 191,204 46,722 42,961 30,374 14,865 13,335

100.0 36.9 26.0 6.4 5.8 4.1 2.0 1.8

839,916 324,100 170,856 78,670 35,221 37,115 22,463 13,298

100.0 38.5 20.3 9.4 4.2 4.4 2.7 1.6

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PREVALENCE OF CAD IN THE ELDERLY While there is general agreement that prevalence of CAD increases markedly with increasing age, the true prevalence of CAD in the elderly is difficult to determine. About 28% of those over 65 die from ischemic heart disease (6,7). Epidemiological studies, relying on history and resting electrocardiographs, have found symptomatic coronary disease in 20–22% of the general population over 70 (25,26). When rest and stress criteria are combined, at least half of those over 70 were found to have CAD (27). Autopsy studies indicate the prevalence of significant CAD (stenosis
60% of at least one coronary artery) to be as high as 60–70% in the elderly (28). EVOLUTION OF THE TREATMENT OF CAD Evolution of the treatment of CAD took place over a period of 200 years. During the 18th century, angina pectoris was recognized as a common and lethal illness that frequently attacked without warning and was associated with sudden death. Its relationship to arterial disease was recognized. During the 19th century, the basic instruments necessary for detecting CAD were developed, as were the basic medications for treating its symptoms. Myocardial infarction (MI) was recognized as a pathological entity. The early and mid 20th century saw the development of sophisticated diagnostic techniques that made modern treatment of CAD and its complications a reality during the last half of the 20th century.

Recognition of Angina Pectoris Twenty-four hundred years ago, Hippocrates noted that frequent attacks of pain in the heart in an old person often predicted sudden death. Treatises describing the pulse and its abnormalities date far back in history, as do descriptions of the anatomy of the heart. Nevertheless, appreciation and understanding of the role of the coronary arteries in the production of cardiac disease did not begin to develop until the late 18th century when Heberden introduced the term angina pectoris (Greek for strangling or choking and breastbone or breast) during a lecture before the Royal College of Physicians of London in July, 1768. He described symptoms he had observed in “at least twenty men almost all above 50 years old, most with a short neck, and inclining to be fat.” Heberden commented that angina pectoris was “not extremely rare,” that it was associated with walking, particularly after eating, and that the uneasiness vanished the moment the patient stood still. He noted the symptoms worsened with time and could occur while lying down. He reported that although the natural tendency of the illness was to kill the patient suddenly, the disorder could last “near 20 years.” Because the patient’s pulse was not usually disturbed by the pain, Heberden concluded that “the heart is not disturbed by it.” He ascribed the illness to “a strong spasm sometimes accompanied by an ulcer,” but commented that he had never had it in his power to “see anyone opened who had died of it.” Heberden published his report in 1772 (29–31). In 1775, Edward Jenner helped his close friend, John Hunter, perform an autopsy on one of Heberden’s patients who had died suddenly following an anginal attack associated with a sense of impending death. Ossified coronary vessels were found but the arteries were not examined carefully. In 1785, Jenner made the connection between angina pectoris and CAD but did not publish his conclusions until 1799 (in a letter to Parry who included it in his text, Syncope Anginosa). John Hunter, who had developed angina

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pectoris in 1773, finally died of the disease in 1793, at age 65. His death occurred suddenly during a dispute with the board of St. George’s Hospital. Jenner’s delay in reporting his conclusions about the basis of angina pectoris until after Hunter’s death has been attributed to his desire not to alarm his life-long friend (32–34).

Defining the Pathophysiology of CAD Although the frightening and disabling nature of angina pectoris was clearly recognized as a major clinical problem during the 19th century; little that was new was added to the basic understanding of CAD during that time. In his 1809 textbook on diseases of the heart, Burns attributed angina pectoris to myocardial ischemia. In 1819, Laennec introduced the stethoscope. In 1840, Williams suggested that obstruction of a coronary artery was the cause of the pallid, yellowish appearance of a segment of myocardium discovered at autopsy. The term myocardial infarction was not then in use (as late as 1884, what is now known as a myocardial infarction was referred to as “fibrinoid degeneration”). In 1867, Brunton introduced amyl nitrite for the treatment of angina pectoris. Nitroglycerin, the mainstay of the treatment of angina pectoris even today, was introduced by Murrell in 1879. Riva-Rocci developed the first practical sphygmomanometer in 1891. The year following the serendipitous discovery of X rays by Wilhelm Conrad Roentgen, in 1895, roentgen studies of the heart were being performed by Williams. That same year, Pierre Marie writing his thesis on complications of cardiac disease used the term MI. Dock, in 1896, was the first physician in the United States to make a diagnosis of coronary thrombosis during life (32,35,36). Widespread appreciation of the relationship between CAD, angina pectoris, and MI did not occur until the second quarter of the 20th century. Sir Clifford Allbutt, in 1900, attributed angina pectoris to disease of the aorta, an understandable conclusion in view of the likelihood of coronary ostial occlusion secondary to the syphilitic aortitis that was so common at the time (36). A major contribution to establishing the pathophysiology of coronary arterial disease was made by Einthoven in 1903, when he developed a practical method for performing electrocardiography. Sir William Osler commented in 1910 that he did not see a case of coronary thrombosis until he became a Fellow of the Royal College of Physicians (37). CAD remained virtually unrecognized as a cause of death until 1912, when Herrick described (in six patients) the clinical features of sudden obstruction of the coronary arteries, including the gross changes that occurred in the myocardium in the region of the infarct. He noted that, while previous attacks of angina had generally been experienced by the patient, fatal coronary arterial thrombosis might be the first evidence of coronary disease (38). In 1918, he republished his data and reported electrocardiographic studies conducted in patients with coronary artery thrombosis (39). White commented that, in the mid 1920s, at Massachusetts General Hospital diagnoses of coronary artery thrombosis and MI were rare among the autopsies performed (31). He stated that he did not see his first patient with a MI until he was in his second year of practice in 1921. In 1923, Wearn wrote that “coronary thrombosis with infarction of the heart as a clinical entity is a condition which is generally classed among the rarities of medicine” (37). The most famous instance of failure to recognize the signs and symptoms of fatal coronary arterial disease occurred in San Francisco on August 2, 1923, when Warren Harding, the 29th president of the United States, died following an acute MI. His death was attributed to acute indigestion or (by the New York Times) to a “stroke of apoplexy.” By the late 1920s, however, coronary thrombosis—alias MI—was a well-established diagnosis.

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Development of Modern Diagnostic Techniques In 1929, a German intern, Werner Forssmann, having heard of an experiment by Claude Bernard, threaded a catheter through his antecubital vein into his right atrium. His goal was to devise a technique to speed delivery of drugs to a patient and, in addition, to understand the mysteries of the heart and circulatory system (40,41). Discouraged from pursuing his experiments by Sauerbruch, the professor of surgery, Forssmann became a urologist. Cournand became aware of Forssmann’s work and by 1941 had developed a technique for catheterizing the right heart in humans (42). Zimmerman in 1950 and Seldinger in 1953 developed the techniques of left heart catheterization. In 1958, F. Mason Sones, Jr., accidentally injected the right coronary artery with contrast material producing the first selective coronary angiogram performed in a human being. Louis Pasteur is credited with the statement “chance favors the prepared mind.” Sones not only recognized the potential value of his serendipitous observation but pursued development of the technique of selective coronary arteriography to make it a practical diagnostic technique. The presentation of his results during the 1959 meeting of the American Heart Association introduced the modern era of medical and surgical treatment of CAD (43).

NATURAL HISTORY OF PATIENTS WITH ANGINA PECTORIS Only 30–40% of 70-year-old individuals with anatomically significant disease of one or more coronary arteries will be overtly symptomatic (with classical angina pectoris or evidence of a MI on a resting electrocardiogram) (25,27). Of those who have symptomatic CAD, about 37% of men and 65% of women will have angina pectoris as the initial manifestation of the disease. If death as an initial manifestation of symptomatic CAD is excluded, then about 40% of men and 70% of women with CAD will be present with angina pectoris as their initial symptom (44,45) (Table 5). Since severe and/or intractable angina pectoris is the major indication for 75–95% of the CABGs performed in the United States, particularly in the elderly, an understanding of the natural history of those with angina pectoris must be the foundation for evaluating the effectiveness of medical or surgical therapy of CAD. Unfortunately, the natural history of angina pectoris is difficult to document. Early studies by Herrick (1918) and by White (1926, 1931, 1943) were handicapped because investigators lacked the technology to determine the extent of disease in the coronary arteries during life (39,46–48). In addition, patients with angina pectoris complicated by associated diseases such as hypertension, valvular heart disease, MI, and CHF were often included with those who suffered from uncomplicated angina pectoris. Table 5 Distribution and Frequency of Initial Manifestations of Coronary Heart Disease in 492 Individuals from the Framingham Study Men Manifestation Angina pectoris Coronary insufficiency Myocardial infarction Death Total

Women

Total

Number

Percent

Number

Percent

Number

Percent

119 23 139 42 323

37 7 43 13 100

110 12 30 17 169

65 7 18 10 100

229 35 169 59 492

47 7 34 12 100

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Table 6 Prognosis of Angina Pectoris: Survival Rates of Patients with Angina Pectoris According to Ages at Time of Diagnosis Percentage alive at Age group (yr) <40 40–49 50–59 60–69 70–79 >80

Number of patients

5 Yr

10 Yr

112 935 2067 2046 572 34

66.1 65.2 61.0 55.4 42.8 26.5

46.5 43.1 37.2 29.0 16.4 13.0

In these early series the annual mortality of patients with angina pectoris ranged from 2.5% to 9.0% (49). In 1952, Block et al. (50) described 5- and 10-year survivals by age group for 6882 patients in whom a diagnosis of angina pectoris had been made. The study population included patients with cardiac enlargement, CHF, and MI. Table 6 summarizes their results. Annual mortality (averaged >10 years) for the entire group was 6.0%. Annual mortality was greatest during the first year (15.3%) then decreased in subsequent years. Overall, 5-year survival for the group was 58%; 10-year survival was 37%. Expected survivals in a general population of like ages would have been 87% at 5 years and 70% at 10 years. In 1971, Gordon and Kannel (44) reported the frequency with which coronary events occurred during a 14-year follow-up of 5209 people randomly sampled from a general population. One hundred and ninety-seven persons developed angina pectoris as their initial manifestation of CAD. The risks of dying in this group of individuals varied with the severity of their symptoms. Annual mortality for those free of heart disease was 1/1000. For those in New York Heart Association (NYHA) class I, the risk of dying was 4/1000/yr; for those in NYHA class II, the risk was 19/1000/yr, and for those in classes III or IV, 43/1000/yr. In 1972, Kannel and Feinleib (45) reported presentations and outcomes in 492 persons who first developed CAD during the 14-year follow-up of a general population of 5127 individuals from the Framingham study (Table 5). Coronary angiography was not performed in these patients. Of the 492 people, 229 presented with angina pectoris. Two hundred of these manifested “uncomplicated” angina pectoris; that is, angina not complicated by MI, coronary insufficiency, or coronary death. Forty percent of the men with uncomplicated angina and 40% of women aged 60 years and older with uncomplicated angina died within eight years. Only 15% of women under age 60 with uncomplicated angina died during the eight years. Annual mortality was 4% for men with uncomplicated angina pectoris. Over a period of five years, MI was relatively uncommon in women with angina pectoris (7%) but occurred in 24% of men. Half of the men over age 45 years with angina suffered a MI within eight years. While studies conducted in the 1950s and 1960s could relate the effects of age, severity of symptoms, and presence of associated cardiac diseases with outcome in patients with angina pectoris, it was not until coronary arteriography became widely available that it was possible to correlate the natural history of these patients with the extent of their coronary disease. In 1972, Oberman (51) analyzed the course of 246 patients with angina but without associated cardiovascular disease or serious noncardiovascular disease. All had undergone coronary arteriography between 1965 and

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1970, a time period prior to the advent of aortocoronary bypass grafting in their institution. At 22 months, there were no deaths in patients with one-vessel disease and small hearts or in those with one-vessel disease and no electrocardiographic evidence of an old transmural infarction. The annual mortality for all patients with one-vessel disease was 2.0%. Annual mortality for patients with two-vessel disease was 13.0% and for threevessel disease, 15.0%. The presence of an old MI, a history of CHF, or an enlarged heart markedly increased the annual mortality in patients with angina pectoris. In 1974, Reeves et al. (49) analyzed the course of 705 patients who had undergone coronary arteriography prior to 1970. The annual mortality for the entire group was 6.5%. For one-vessel disease, annual mortality was 2.2%; for two-vessel disease, 6.8%; and for three-vessel disease, 11.4%. In 1983, Proudfit et al. (52) presented 15-year survivals for 598 patients with chest pain treated medically following angiography. All but 64 were male. Annual mortality averaged over 10 years was 5.4% with a 31% 15-year survival. Overall, the natural history of most patients with angina pectoris is poor with annual mortality rates for uncomplicated disease of 4–6%. However, angina pectoris alone is a poor predictor of survival (53). Individuals with single-vessel disease and angina pectoris uncomplicated by a history of transmural MI, CHF, cardiomegaly, associated cardiovascular disease, or serious noncardiovascular disease appear to have annual mortality rates of 1% or less (49). In the study by Oberman et al., the independent predictors of increased annual mortality in patients with angina pectoris followed for 22 months, in the order of their importance, were heart size, stenosis of the left anterior descending artery, dyspnea on effort with either paroxysmal nocturnal dyspnea or orthopnea, heart rate, stenosis of the left main coronary artery, stenosis of the left circumflex artery, and stenosis of the right coronary artery (51). The need to identify subsets of patients with CAD was to assume greater importance as the outcomes of CABG and percutaneous transluminal coronary angioplasty (PTCA) began to be evaluated. EVOLUTION OF SURGICAL TREATMENT At about the time of Herrick’s report that sudden occlusion of a major coronary artery was not “almost universally fatal,” surgeons began their attempts to relieve the pain of angina pectoris. Franc¸ois-Franck, in 1899, proposed removal of the cervical and first thoracic ganglia. His intent was to accomplish a complete cure of certain cases of Graves’ disease, which were complicated by aortitis and angina (54). Bilateral extirpation of the cervical sympathetic chain, together with removal of both thoracic ganglia for the treatment of angina pectoris, was first performed by a Bucharest surgeon, Jonnesco, in 1916 (55). From 1916 through 1982, no less than 59 different varieties of surgical procedures were performed for the treatment of CAD. The procedures ranged from those designed to interrupt the afferent nerve pathways from the heart to those developed to replace the heart. These surgical approaches to CAD can be divided into four broad categories: extrapericardial procedures, techniques for indirect myocardial revascularization, direct revascularization of the coronary arteries, and cardiac replacement (41,56–58) (Table 7). A few of these procedures were performed only in experimental animals; some represented variations of a more basic concept; many were devised by more than one individual; most were performed in humans at one time or another often over a period of many years. Eventually, all but a few were found to be ineffective or minimally effective. A major share of the credit for the development of modern coronary arterial surgery belongs to Claude Beck of Western Reserve University and to his persistent efforts to prevent sudden death in patients with a heart “too good to die.” Beginning in 1935, he

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Table 7 Classification of Surgical Procedures Designed to Treat Coronary Artery Disease 1. Extrapericardial procedures A. Denervation procedures B. Procedures to decrease metabolic demand of myocardium C. Procedures to redirect blood flow to coronary arteries 2. Indirect myocardial revascularization procedures A. Cardiopericardiopexy procedures B. Epicardial grafting procedures C. Procedures to increase retrograde flow into native vessels D. Procedures to increase oxygen extraction E. Procedures to stimulate collateral development F. Myocardial channelization procedures G. Myocardial implant procedures 3. Procedures for direct revascularization of the coronary arteries A. Angioplastic (endarterectomy) procedures B. Replacement grafting C. Bypass grafting 4. Cardiac replacement A. Transplantation B. Mechanical heart

devised and applied numerous variations of his Beck I and Beck II operations. He noted that increases of arterial flow of as little as 5 mL/min into anoxic areas of the myocardium could relieve the pain of angina pectoris and could afford protection against a fatal heart attack (59,60). About 10 years later, Arthur Vineberg of Montreal began advocating implantation of systemic arteries into the myocardium, thus beginning the era of indirect myocardial revascularization (61). Two sentinel events in the 1950s made possible the modern era of myocardial revascularization. On May 6, 1953, the ability to operate on a quiet heart free of blood became a reality when John Gibbon successfully closed an atrial septal defect using a heart lung machine he and his wife had developed (62,63). In 1958, F. Mason Sones, Jr., provided the means to accurately identify, localize, and quantify coronary artery lesions (43,64). Widespread application of the current techniques of direct myocardial revascularization began after the reports of Favoloro, Johnson, Urschel, and Kerth in 1969 (64–67). The first transplantation of a human heart was performed by Christiaan Barnard in South Africa in 1967 (68). On September 16, 1977, Andreas Gruentzig, in Zurich, performed the first balloon dilatation of a coronary artery in a human. The technique was referred to as PTCA and was quickly adopted as an alternative to CABG (41). In the mid-1970s, 70,000 CABGs were performed annually in the United States (64). By 1994, the number had grown to 318,000 per year (69). As early as 1971, however, there were those who questioned the efficacy of aortocoronary bypass grafting and the justification for its widespread application. The objections and criticisms were based in part on the past history of failures and marginal results of surgical procedures intended to treat CAD, in part on what were considered to be the high risks inherent in coronary artery surgery, and in part on the availability of techniques of medical management that presumably could yield results comparable with or superior to those achieved by operation. These concerns led to the performance of numerous controlled studies that compared the outcomes of medical and surgical therapy.

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The advent of PTCA led to additional randomized studies comparing PTCA with CABG and with medical treatment. OUTCOME OF RANDOMIZED STUDIES Since 1972, five large randomized studies have compared the results of coronary arterial bypass plus medical therapy with intensive medical therapy of angina pectoris. Stable angina pectoris was the subject of three studies; unstable angina was the subject of two studies. More recently, two more randomized studies have compared outcomes in patients treated by PTCA and CABG. While various criticisms can be made of the design and conduct of these studies, it is important to summarize their findings since the conclusions drawn from them have shaped the indications for CABG in patients of all ages. Early Veterans Administration Studies In the mid-1960s, cardiologists and thoracic surgeons in the Veterans Administration (VA) developed a keen interest in evaluating current surgical procedures to revascularize the ischemic heart. Three operations were studied, each in increasing detail, employing randomization techniques: The Beck “poudrage” procedure, the Vineberg implant procedure, and direct revascularization procedures. Analyses of the Beck procedure did not reach the literature. In the study of the Vineberg procedure, a total of 146 patients (75 medical and 71 surgical) were randomized between 1966 and 1972. Thirty-day operative mortality (OM) was 12.3%. Visualization of the implant one year after operation was accomplished in half of the eligible patients. Fifty percent of the patients with single implants and 69% of those with double implants were found to have patent grafts. At 12 years, 41% of the medical group and 42% of the surgical group were alive. Eighty-one percent of the deaths in both the medical and surgical groups were due to cardiac disease. The degree of revascularization achieved by the implants did not improve survival. The study ended partly because of these findings and partly because of the shift to direct revascularization of the coronary arteries (70). VA Stable Angina Study Six hundred and eighty-six patients were entered into the stable angina study between 1972 and 1974. Three hundred and fifty-four individuals were randomized to medical therapy; 332 were randomized to medical plus surgical therapy. Ninety-one patients had greater than 50% stenosis of the left main coronary artery (43 medical, 48 surgical). Five hundred and ninety-five patients were “non–left main” (311 medical and 284 surgical). All patients were men. There were no age restrictions. The age range of those in the study was 27 to 68 years with a mean age of 50.5 years. Forty-four percent of the patients were less than 50 years old. Patients with all degrees of angina were accepted. There was no minimum ejection fraction set for selection. During 11 years of follow-up, 38% of the 354 patients assigned to medical treatment underwent bypass surgery. Twenty-two of those crossing over had left main CAD. At 11 years, survival for patients without significant left main disease was 58% in both treatment groups. Survival between treatment groups of patients with one-vessel or three-vessel disease was not significantly different at either 7 or 11 years. At 11 years, survival for patients with two-vessel disease treated surgically was marginally worse than for their counterparts treated medically (55% vs. 69%; p ¼ 0.045). Patients treated

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surgically for left main disease clearly did better than those treated medically (88% vs. 65%, p ¼ 0.016). Patients who were categorized as high risk by angiographic and/or clinical criteria had significantly better survival with surgical treatment. Patients were classified as angiographically high risk if they had three-vessel disease and impaired left ventricular function. They were classified as clinically high risk if they had at least two of the following: resting ST depression, a history of MI, or a history of hypertension. Survival at 11 years in the high clinical risk group was 49% for the surgical group and 36% for the medical group ( p ¼ 0.015 ). In the low clinical risk group, survival at 11 years was 63% for the surgical group and 73% for the medical group ( p ¼ 0.066). In the angiographic high-risk group, survival at 11 years was 50% for surgical patients and 38% for medical patients ( p ¼ 0.026). In the angiographic low-risk group, the corresponding survival data were 61% and 68% ( p ¼ 0.105). In the combined high angiographic and clinical risk group, survival at 11 years was 54% in the surgical group and 24% in the medical group ( p ¼ 0.005). Corresponding survivals in the combined low angiographic and clinical risk group were 66% and 76% ( p ¼ 0.092). The average annual mortality rates during the first seven years of the study were 3.3% for all surgically treated patients without left main disease and 4.0% for all medically treated patients without left main disease. During the next four years, the corresponding annual mortality rates were 4.8% and 3.5%. Thus, three groups of patients benefited from surgical treatment: those with significant left main disease; those with extensive coronary arterial disease associated with reduced ventricular function; and those who fell into clinical or angiographic high-risk categories. Quality of life was better in those patients treated surgically. At 5 years, 41% of surgical patients and 17% of medical patients reported marked improvement in symptoms. Twenty percent of the surgical patients and 42% of the medical patients described worsening symptoms. Over the five-year period, the benefits of surgery decreased, but at 5 years were still significantly better than medically treated patients ( p ¼ 0.0014). The incidence of nonfatal MI was not significantly different between the two treatment groups. At five-year follow-up, left ventricular function remained unchanged in both treatment groups (71–74).

VA Unstable Angina Study Four hundred and sixty-eight patients were entered into the unstable angina study between 1976 and 1982 (237 medical, 231 medical plus surgical). Three hundred and seventy-four patients were identified as Type I (accelerated angina, rest angina, and recent-onset angina); 94 were identified as Type II (prolonged angina unrelieved by nitrates and accompanied by ST-segment changes on electrocardiogram). All patients were men. There were no age restrictions. The age range in the study was 32 to 73 years, with a mean age of 56 years. Patients with all degrees of angina were accepted. Patients with ejection fractions below 30% and those with left main lesions greater than 50%, recent MI, or prior coronary artery surgery were excluded. At the end of 10 years, 50% of patients randomized to medical treatment had crossed over to surgery. At 10 years, survival was 61% for surgical patients and 62% for medical patients. At five years and eight years, there was significantly better survival for patients with threevessel disease treated surgically (89% vs. 77% and 77% vs. 65%, respectively). At 10 years, however, the surgical advantage was no longer significant (63% vs. 57%; p ¼ 0.190). At eight years, survival of patients with three-vessel disease and an ejection fraction of 58% or less was significantly better in the surgical group (79.5% vs. 57.1%; p ¼ 0.018). In contrast, survival at eight years in those with one- or two-vessel disease and

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an ejection fraction greater than 58% was significantly better with medical treatment (83.2% vs. 67.8%; p ¼ 0.022). A major finding in this study was the effect of surgical treatment on survival of patients with an ejection fraction between 30% and 58% if the crossovers from medicine to surgery were censored (counted as lost to follow-up at the time of crossover). When this was done, there was a strong advantage to surgical treatment throughout the 10 years of follow-up (59% vs. 43%; p ¼ 0.007) (75). Continued smoking was an independent predictor of death in the surgical group at 2, 5, and 10 years. At 10 years, NYHA class III or IV, age, and diabetes mellitus (DM) were additional independent predictors of mortality in the surgical group. In the medically treated group, decreased ejection fraction and the number of vessels diseased were consistent, independent predictors of mortality. As in the stable angina study, quality of life was better in the surgical patients who had superior pain control, reduced medication requirements, and significantly fewer new cardiovascular hospitalizations over the 10-year observation period ( p ¼ 0.0001). At the end of 10 years, the number of nonfatal MIs was not significantly different between the treatment groups (76–79).

EUROPEAN CORONARY SURGERY STUDY GROUP Seven hundred and sixty-eight patients were entered into the study between 1973 and 1976 (373 medical, 395 surgical). One patient was lost to follow-up before operation, leaving 394 surgical patients. All were men under the age of 65 years (mean age 50 years). Those with severe angina pectoris as well as those with ejection fractions below 50% or single-vessel disease were excluded from the study. Patients with left main lesions of 50% or more were included on a discretionary basis (31 medical, 28 surgical patients). Those assigned to medical treatment could cross over to the surgical group if they had unacceptable symptoms despite adequate medical therapy (24% did cross over within five years). All patients were followed for five years; 60% were followed for six years; 25% for seven years; and 10% for eight years. At five years, 92.4% of the surgical patients and 83.6% of the medical patients were alive ( p ¼ 0.00025). In those patients with left main disease, there was a markedly increased five-year survival with operation, but because of the small numbers, the difference was not significant (81.7% vs. 67.9%; p ¼ 0.11). Survival was markedly improved in the surgical group with three-vessel disease and also in the group with twoor three-vessel disease when it was associated with stenosis of 50% or greater in the proximal left anterior descending artery. An abnormal electrocardiogram, ST-segment depression of 1.5 mm or more during exercise, and the presence of peripheral vascular disease were each independent predictors of better survival with operation. Survival at 10 years in patients over the age of 53 years was significantly better in the surgical group (72% vs. 57%; p ¼ 0.007). Below age 53 years, age was not a significant factor affecting outcome between the two treatment groups. A conclusion drawn from the study was that the greatest benefits of surgery occurred in the high-risk groups of patients. Surgery was unlikely to improve five-year survivals in patients with good left ventricular function, ST-segment depression less than 1.5 mm on exercise, a normal resting electrocardiogram, and absence of peripheral vascular disease. These conclusions closely resemble those reached in both the stable and unstable VA randomized studies (79–82). Operation markedly improved the quality of life as measured by the percentage of patients free of angina or by the degree of increased exercise tolerance. As in other

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studies, these effects diminished with time, although the advantage over medical treatment remained statistically significant at four years for exercise performance ( p ¼ 0.001) and throughout the study for relief of angina ( p ¼ 0.001) (80). Coronary Artery Surgery Study In 1973 the National Heart, Lung, and Blood Institute organized a randomized trial designed to compare results of medical and surgical therapy in patients with CAD. The goal of the randomized trial was to test the hypothesis that coronary artery bypass surgery significantly reduced the mortality rate and the incidence of MI in patients with mild angina or in those who were asymptomatic after a MI (but who had CAD documented by angiography) (82,83). Between 1975 and 1979, 780 patients were entered into the study (390 medical, 390 surgical). Ninety percent of the patients were men. All enrollees were 65 years of age or less; the mean age was 51.2 years. Patients with angina more severe than Canadian class II were excluded, as were those with unstable angina, progressive angina, CHF, previous coronary bypass surgery, or serious coexisting illness. Patients with an ejection fraction less than 35% and those with left main lesions greater than 70% were also excluded. Patients with a well-documented MI more than three weeks before randomization were accepted into the study. Analyses were performed on the basis of treatment assigned (79,83). At eight years, 87% of the surgical patients and 84% of the medical patients were alive ( p ¼ 0.14). However, in the subset of patients with ejection fractions below 50%, 84% of the surgical patients and 70% of the medical patients were alive at seven years ( p ¼ 0.012). When this subset of patients was analyzed by the number of vessels diseased, a significant difference in survival was found only in those patients with three-vessel disease (88% in the surgical group, 65% in the medical group; p ¼ 0.0094). There was no significant difference between the medical and surgical treatment groups in the occurrence of nonfatal MI. At five years, the crossover rate from medicine to surgery was 24% (82). From the standpoint of quality of life at five years, the surgical group had significantly less chest pain ( p < 0.0001), fewer limitations of activity ( p < 0.0001), and a lower requirement for b-blockade ( p < 0.0001). In the surgical group, treadmill exercise tests documented less exercise-induced angina, less ST-segment depression, and longer treadmill times (84). National Cooperative Study Group: Unstable Angina Under the auspices of the National Heart, Lung, and Blood Institute, a prospective, randomized study was initiated comparing intensive medical therapy with urgent coronary arterial bypass for the management of patients with unstable angina. Between 1972 and 1976, 288 patients were entered into the study (147 medical, 141 surgical). Eighty-two percent were men. All enrollees were under the age of 70 years. The patients had to have angina associated with transient ST-segment or T-wave changes on electrocardiogram. Ninety percent of the patients had rest pain while in the hospital. Although the patients had to have greater than 70% occlusion of at least one coronary artery to be eligible for randomization, 76% had multivessel CAD. Thirty percent of the individuals in the study had proximal left anterior descending arterial disease. Thus, the group corresponded to patients with Type II symptoms in the VA unstable angina study. Ejection fractions of 30% or less or greater than 50% narrowing of the left main coronary artery were reasons for exclusion as were an MI within three months or serious illnesses other than CAD.

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At 65 months, there was no significant difference in survival between surgical and medical patients (85% surgery vs. 84% medical). Forty-three percent of patients crossed over from medicine to surgery (34% of those in NYHA classes I and II and 60% of those in NYHA classes III and IV). Crossover occurred sooner in patients with more severe angina (85). As was the case in the other randomized studies, quality of life was better in the surgical group. At the end of the first year, severe angina was significantly more common in the medical group in patients with one-vessel disease ( p < 0.05), two-vessel disease ( p < 0.01), and three-vessel disease ( p < 0.01). There was no significant difference in the incidence of nonfatal MI between the two treatment groups (86).

Emory Angioplasty Versus Surgery Trial The Emory Angioplasty versus Surgery Trial (EAST) study was designed to determine whether initial revascularization with angioplasty in patients with multivessel coronary disease was a viable alternative to bypass surgery on the basis of outcome at three years. Between 1987 and 1990, 5118 patients were screened. Exclusion criteria included left main disease, two or more total occlusions of the coronary vessels, an ejection fraction less than or equal to 25%, recent MI (within five days), insufficient symptoms, and lifethreatening noncardiac illnesses. Advanced age was not a criterion. Three hundred and ninety-two patients were randomized, 198 to PTCA and 194 to CABG. All had two- or three-vessel disease. The mean age of the PTCA patients was 61.8 years. The mean age of the CABG patients was 61.4 years; 74.7% of the PTCA patients and 72.7% of the CABG patients were men. Data were analyzed according to intention to treat. OM was 1% in both groups. In-hospital Q-wave MIs were suffered by 10.3% of CABG patients and 3.0% of PTCA patients. Ten percent of the PTCA patients required CABG at the time of initial revascularization. Within three years 6.2% of the CABG group had died compared with 7.1% of the PTCA group ( p ¼ 0.72). 19.6% of the CABG patients had suffered a Q-wave MI compared with 14.6% of those treated by PTCA ( p ¼ 0.21). During the three-year followup, 1% of the CABG group and 22% of the PTCA group required CABG. Thirteen percent of the CABG group and 41% of the PTCA group required PTCA. In terms of quality of life, the CABG group had a better outcome than the PTCA patients. Twenty percent of those treated by PTCA were in Canadian Cardiovascular Society classes II, III, or IV compared with 12% of those treated by CABG ( p ¼ 0.039). Sixty-six percent of the PTCA group and 51% of the CABG group required antianginal medication ( p ¼ 0.005). Median initial procedure costs (in 1987) for PTCA were $14,166 compared with $22,894 for CABG. At three years, the median costs for treating a PTCA patient totaled $19,059; those for a CABG patient totaled $23,572. Procedure costs included physician and hospital costs (87,88). The Bypass Angioplasty Revascularization Investigation In 1987 the National Heart, Lung, and Blood Institute initiated the Bypass Angioplasty Revascularization Investigation (BARI) study to test the hypothesis that, during a fiveyear follow-up period, PTCA does not result in a poorer clinical outcome than does CABG in patients with multivessel coronary disease and severe angina or myocardial ischemia. Between 1988 and 1991, 1829 patients were randomized: 914 to CABG and 915 to PTCA. Mean age of the CABG patients was 61.1 years. That of the PTCA patients

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was 61.8 years. Seventy-three percent of the PTCA patients and 74% of the CABG patients were men. Data were analyzed according to the intention-to-treat principle. OM was 1.3% in the CABG group and 1.1% in the PTCA group; 4.6% of the CABG group and 2.1% of the PTCA group suffered a Q-wave MI ( p ¼ 0.004). Of all patients assigned to PTCA, 12.8% had additional revascularization procedures during the initial hospitalization; 6.3% of the PTCA patients required emergency CABG. Cumulative survival rates at five years were 89.3% for CABG patients and 86.3% for PTCA patients ( p ¼ 0.19). Rates of survival free of Q-wave infarction at five years were 80.4% for those treated by CABG and 78.7% for those treated by PTCA ( p ¼ 0.84). Cumulative rates of Q-wave infarction at five years were 11.7% for CABG and 10.9% for PTCA ( p ¼ 0.45). During the five-year follow-up, 54.5% of the PTCA patients required revascularization procedures compared with 8.0% of the CABG patients. Nineteen percent of the PTCA group required multiple revascularization procedures compared with 3.0% of the CABG group. Improvement in functional status (as measured by the Duke Activity Scale) was better in the CABG patients (5.6 units vs. 3.2 units; p ¼ 0.04). Mean initial procedure cost for PTCA was $21,113 compared with $32,347 for CABG. At five years, the total mean costs for PTCA were $56,225 compared with $58,889 for CABG. A major finding in this study was the difference in survival at five years between treated diabetics assigned to PTCA and treated diabetics assigned to CABG (65.5% for PTCA patients vs. 80.6% for CABG patients; p ¼ 0.003). The term treated diabetics referred to those requiring insulin or oral hypoglycemic agents. As is true in most studies, the overall survival at five years for diabetics was less than that for nondiabetics (73.1% vs. 91.3%) (12,88,89). Overview While the general goal of each of the randomized trials summarized above was to compare the results of medical and surgical treatment of coronary arterial disease, it is clear that the individual studies differed substantially in mortality data, study design, patient selection, and patient recruitment. It is nevertheless striking that there are a number of major conclusions for which there is substantial agreement among the studies. 1. Angina pectoris is not in itself an indication for CABG except for the quality of life. Surgical treatment for this purpose had a significant advantage in each of the trials. 2. CABG does not increase survival over that obtained by medical therapy for oneor two-vessel disease unless the patient falls into a high-risk category. 3. CABG has a clear advantage over medical management in the treatment of significant left main disease. 4. CABG results in a significantly increased survival when compared with medical management in patients with three-vessel disease and abnormal left ventricular function. 5. CABG results in better survival than medical management in patients who are high risk by clinical or angiographic criteria, or a combination of both. 6. Quality of life is uniformly better in the group treated by CABG. Exercise tolerance and freedom from angina are better in the surgical group. Requirements for medication and new hospitalizations for cardiovascular events are less in the surgical group. 7. In those groups that benefited from CABG, the benefits, particularly as they concern quality of life, tend to decrease with time. Even so, the advantages of CABG continue for 5 to 10 years.

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8. When analyzed on the basis of intent-to-treat, there is no difference in three- to five-year survival of patients randomized to PTCA or CABG as the initial treatment for multivessel disease. 9. Over a three- to five-year period, there is no difference in the rate of Q-wave infarctions in patients initially randomized to PTCA or CABG. 10. Patients undergoing PTCA as the initial treatment for multivessel disease require additional revascularization procedures much more frequently than those initially treated by CABG. 11. Initial costs of PTCA are lower than those of CABG, but at five years the total costs are about equal. 12. Diabetics requiring insulin or oral hypoglycemic agents fare better with CABG than PTCA for multivessel CAD. THE ELDERLY AS CANDIDATES FOR CABG The five randomized studies comparing CABG with medical treatment were conducted in the 1970s in a younger, primarily male population. Mean ages in the five studies varied from 50 to 56 years. Patient outcomes in that group were used to determine indications for surgery. The current population undergoing CABG, however, has a different composition. It is older (mean age 65 years) and has a larger percentage of women (30%). Reports of outcomes following CABG in 70-, 80-, and even 90-year-olds are easily found in the literature but determining the benefits of CABG in this group and establishing indications for operation in the elderly necessarily involves an appreciation of the nature and extent of CAD in the patient population at risk. Table 8 compares by Table 8 Baseline Characteristics of Patients Undergoing Cardiac Catheterization for Ischemic Heart Disease 1/1/95 Through 12/31/98 (21,573 Patients) Prevalence (%) Factor Number of patients Female gender Severity of disease Left main disease Three-vessel disease 30%< EF <50% Clinical indication Myocardial infarction Unstable angina Stable angina Complications CAD Prior myocard infarction Hx congest heart failure Comorbidity Diabetes mellitus Cerebrovascular disease Peripheral vascular disease Chronic pulmonary disease Hypertension

<70 yr

70–79 yr

>80 yr

15392 26.0

5198 36.4

983 44.2

6.3 18.1 20.5

11.3 22.9 23.4

13.9 24.3 22.2

27.1 28.4 32.1

25.5 34.0 29.7

31.8 37.8 21.3

49.5 10.5

53.5 20.3

59.1 30.5

17.4 4.2 5.7 7.3 48.8

20.4 8.7 8.8 12.4 56.9

18.4 11.5 11.7 13.5 57.7

Abbreviations: CAD, coronary artery disease; EF, ejection fraction. Source: From Ref. 90.

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age group the baseline characteristics of 21,573 patients undergoing cardiac catheterization for ischemic heart disease. Approximately half of these patients were managed medically. The remainder underwent either percutaneous coronary intervention (PCI) or CABG. It is apparent that older patients present for operation with more advanced coronary disease, more complications from their heart disease, and a greater number of coexisting diseases (90). The prevalence of angina pectoris in the general population in the United States is approximately 1%. Prevalence increases with increasing age, afflicting 9.2% of a general population 55 to 69 years old and 14.7% of a general population 70 to 88 years old ( p ¼ 0.0002) (53). Even so, the prevalence of ischemic heart disease increases more rapidly with age than angina (3), indicating that CAD in the elderly is more likely to be present with manifestations other than uncomplicated angina. Silent ischemia affects about 30% of the population over 70 years of age in contrast to 10% of a population in its 50s (25,26,91–94). Silent ischemia is not a benign event, even in the middle aged, but it is much more dangerous in the elderly. In Erikssen and Thaulow’s study of younger patients (91), there was 0.5% incidence of sudden death. Cardiac events occurred in 21–46% of younger patients with silent ischemia (92). In a study by Aronow (95), the prevalence of sudden death and coronary events in octogenarians was 38% and 69%, respectively, during 43 months of follow-up. MI is not only more common in the elderly, but also it often goes unrecognized (39% of those over 65 vs. 27% of those under 65) (96,97). Dyspnea rather than chest pain becomes the predominant symptom of an acute MI in those over the age of 80 (98,99). Compared with a younger population, the elderly also have a higher mortality after infarction (12–39% vs. 2.0–8.0%) and a higher incidence of complications secondary to the infarction (99,100). CHF is more common in older individuals with an annual incidence rising from 2/1000 in men 45 to 64 years old to 8/1000 in those 65 to 74 years old, 14/1000 in those 75 to 84 years old, and 54/1000 in those 85 to 94 years old. Women over the age of 75 years have a similar or greater rate of incidence. Mortality from CHF in those aged between 65 and 94 years is 88% within six years (101). The incidence of sudden death from CAD in a general population rises from 1.1/1000 in men 45 to 54 years old to 2.6/1000 in men 65 to 74 years old. In women, the respective incidences are 0.3/1000 and 1.2/1000. The percentage of coronary attacks (death and/or MI) whose initial manifestation is sudden death increases from 13.6% in men 35 to 44 years old to 20% in men over 65 years old. The probability of sudden death also increases with the duration of uncomplicated angina (2.6% at two years; 9.7% at seven years). Males who have heart disease and are hypertensive, diabetic, and cigarette smokers represent an identifiable group who are at high risk for sudden death. The risk of sudden death over the age of 65 years is three to four times higher in men with CAD and two to seven times higher in women with CAD than it is in those without CAD (102,103). Table 9 represents a composite of 34 nonrandomized studies reported between 1982 and 1997 of patients who had undergone CABG. It compares the characteristics of a population under age 70 with those of a population over 70. While there is considerable overlapping of data, it is apparent that those over age 70 are more likely to have a history of CHF and a higher prevalence of left main disease, three-vessel disease, and impaired left ventricular function. In addition, more of the elderly are operated upon urgently or emergently, a circumstance that in itself will double or triple their OM (104).

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Table 9 Characteristics of Patients Undergoing Coronary Bypass Grafting: Comparison of Those Aged Less Than 70 years with Those Aged 70 Years and Older Prevalence (%) Under 70 yr Factor Female gender NYHA IV Left main disease Three-vessel disease 30%< EF <50% Prior myocardial infarction Hx congestive heart failure Diabetes mellitus Cerebrovascular disease Peripheral vascular disease Urgent or emergent surgery

70 yr or Older

Range

Mean

Range

Mean

13.0–38.7 23.0–56.0 7.0–20.9 40.8–78.0 19.7–42.0 35.0–62.0 3.0–33.6 4.0–28.0 – 4.4–13.0 6.0–41.0

28.3 44.8 13.1 49.0 24.6 57.4 9.7 16.1 6.0 4.4 9.5

24.6–46.0 20.0–63.0 3.4–35.0 27.0–90.0 22.0–66.0 22.8–68.5 7.0–67.0 3.0–60.0 6.4–21.0 4.2–26.0 7.0–56.8

27.8 36.7 16.4 61.9 33.3 53.6 17.1 12.6 9.0 5.4 17.3

Abbreviations: NYHA, New York Heart Association; EF, ejection fraction; Hx, History.

OUTCOME Effectiveness of CABG in the elderly must be measured against the results of alternative treatments such as PTCA, maximal medical management, or routine symptomatic treatment. When costs are being compared, expenses of treatment over a period of years must be considered rather than just those of the initial episode. Mortality and morbidity are the obvious short-term measurements to be made. The critical long-term measurements are survival and quality of life. Survival must not only be measured against that of the general population of similar age, but against the projected survival of a population in which CAD was allowed to pursue its natural course. Quality of life includes measurements such as relief of symptoms, freedom from further coronary events, and improvement in functional capacity. Costs are of concern to patients, their families, and society as both a practical matter and a philosophical issue.

Baseline Data Table 10 depicts both expected survivals for a general population age 60 years in 1940 and for individuals in a general population of selected ages in 1992. The same table also depicts the expected survivals of patients with angina pectoris prior to the advent of modern medical and surgical treatment. The data reported by White (48) and Block (50) excludes patients with valvular disease, but includes some patients with a history of MI, CHF, hypertension, and diabetes. The data reported by Kannel (45) represents survivals of patients with uncomplicated angina pectoris; that is, patients without valvular disease, MI, or the coronary insufficiency syndrome. While the data from White and Block are older (30s and 40s) than those from Kannel, the composition of their patient populations more closely approximates that of current populations undergoing CABG. The two sets of data represent the extremes of outcome against which the results of medical and surgical treatment can be evaluated.

1940 1992 1992 1992 1992 1992 1931 1927–1944 1949–1952 1944 1944

Reference year 60 50 60 70 80 80–89 56.5 58.8
50, men 68 68

Age of population General population General population General population General population General population General population Natural Hx angina pectoris Natural Hx angina pectoris Natural Hx uncomplicated AP NDþCAD DMþCAD

Nature of population

5 87.6 97.2 93.2 85.3 68.5 62.0 64.2 58.4 84.0 75.0 63.0

1 98.2 99.5 98.8 97.3 94.0 92.0 89.3 84.7 100 — —

72.0 92.9 83.8 67.2 — — 39.8 37.1 58.0 55.0 39.0

10

53.3 86.6 71.5 46.1 — — 19.5 22.1 — 34.0 21.0

15

33.2 77.9 56.4 — — — 12.7 14.1 — — —

20

Abbreviations: CAD, coronary artery disease; NDþCAD, nondiabetic patient with CAD treated either medically or surgically; DMþCAD, diabetic patient with CAD treated either medically or surgically; Uncomplicated AP, angina pectoris uncomplicated by myocardial infarction, coronary insufficiency, or coronary death.

Life Tables US Life Tables US Life Tables US Life Tables US Life Tables US Life Tables US White, Bland Block Kannel Barzilay Barzilay

Source

Percentage survival at specified intervals (yr)

Table 10 Survival Data: General Population, Natural History of Population with Angina Pectoris, Diabetic Population with CAD

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Operative Mortality Reported OM following CABG in the elderly varies widely as a result of differences in patient selection. Advanced cardiac disease, high prevalence of associated diseases, and the need for urgent or emergency operation are the major factors that increase mortality in the elderly. Table 11 (104–110) is a composite of operative mortalities reported in various age groups undergoing elective or emergency operation. It is apparent that OM increases with advancing age and the priority of the procedure. Performing CABG urgently or emergently in the elderly is associated with a very high OM. Table 12, a compilation of data from Curtis et al. (106), Peterson et al. (107), and He et al. (111), lists the effects of selected factors on OM following CABG in the elderly. Again, performing CABG as an urgent or emergency procedure clearly has the greatest adverse effect on OM. Dziuban (112), describing his group’s experience with 460 patients, found an OM of 1.2% following elective CABG; 3.2% after urgent CABG, and 26% if the operation was performed as an emergency. In series in which the adverse factors listed in Table 12 were not significantly higher in elderly patients, operative mortalities of 1.0–1.3% were reported in groups of patients with a mean age of 61 and 1.0–4.2% in those aged 70 and above (13,89,108,113). DM treated with insulin or oral hypoglyceric agents is associated with an increased 30-day mortality following CABG. Carson (114), reporting outcomes in 146,786 patients with a mean age of 65 years, found that OM in those without DM was 2.7%. Thirty-day OM with DM controlled by oral medications was 3.2% while OM in insulin-dependent diabetics was 4.6%.

Table 11 Summary of Reported Operative Mortality Following Coronary Artery Bypass by Age Groups 30-Day operative mortality (%) Priority of operation

50

<70


70


80

Overall Elective Urgent or emergent

0.6–3.0 0.4–0.7 2.2–4.8

1.0–5.2 0.6–1.6 4.9–5.1

1.8–12.0 1.0–4.2 4.1–22.2

2.0–24.0 0.0–8.0 8.8–28.6

Table 12 Relative Effects of Selected Factors on 30-Day and 3-Year Mortality Relative mortality Factor Urgent or emergent operation Cigarette smoking Chronic renal failure Hx myocardial infarction Cerebrovascular disease Congestive heart failure Peripheral vascular disease Age Female gender Pulmonary disease Abbreviation: Hx, history.

30 days 4.50 2.69 2.42 2.33 2.22 1.77 1.42 1.37–3.50 1.19–2.90 0.96

3 yr

2.38 1.70 1.73 1.33 1.33 1.33 1.11

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Table 13 Summary of Reported Morbidity Following Coronary Artery Bypass by Age Groups Prevalence (%) Complication Overall Cardiac Atrial arrhythmia Ventricular arrhythmia Perioperative MI Pulmonary Stroke Renal failure GI bleeding Sepsis Pneumonia Wound infection

50

<70

>70


80

0.6–26.0

16.0–20.0

20.0–58.0

54.0–73.0

— 6.0 1.8–6.0 3.7 0.0–2.4 1.2 — — — 2.5

4.0–8.0 — 0.9–7.0 41.0 0.7–2.0 0.3–3.5 0.9–1.6 0.0–1.2 3.4 2.5

11.0 — 0.0–9.9 — 1.3–6.5 0.9–3.5 1.8–4.3 1.2–1.4 4.4–6.5 5.4

19.0–42.0 6.0–8.0 1.4–13.0 20.0–36.0 1.3–5.6 6.3–19.0 — 7.0 14.0 3.9–5.0

Morbidity After CABG Overall postoperative morbidity in the elderly can be as high as 65%. Nineteen percent of the complications are life threatening, while 30% of patients have two or more complications (115). Table 13 summarizes morbidity following CABG (108–110,116–124). It is apparent that the overall frequency of complications increases with age over 70 years. The most common minor complications over age 70 were cardiac arrhythmias. Atrial fibrillation occurred in 10–40% of patients (109,113,125). Major complications were suffered by 22–24% of those older than 70 years (120,125). The most common major complications were MI, pneumonia, and stroke. Carson (114), reporting morbidity, infection, and septicemia rates in 146,786 CABG patients with an average age of 65 years, noted that the risk of infection and other serious life-threatening complications was 36–38% higher in diabetics treated with insulin or oral agents even after adjusting for differences in risk factors.

Survival Table 14 summarizes survival data from several authors (90,110,113,117,118,121,126–128). Again, there is some variation as a result of patient selection, but it is clear that long-term survival following CABG of those aged 70 years or older as well as those in their 80s closely approximates that of a general population of like age (Table 10). It is also clear that survival of patients after CABG is markedly better than would have been the case if the angina had been allowed to pursue its natural course (Table 10). Although most authors have reported a higher OM in women, long-term survival of women following CABG is at least as good as that of men in all age groups (116) (Table 15). Increasing age, ejection fraction below 35%, severe wall motion abnormalities, endsystolic volume greater than 80 mL, and the presence of two or more associated medical conditions are predictors of decreased long-term survival (126,129). Over age 65 years, 45% of late deaths are due to noncardiac causes. Below age 65 years, 29% of late deaths are due to noncardiac causes. Diabetics with CAD, particularly those requiring insulin or oral hypoglycemic agents, have a decreased long-term survival regardless of the method

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Table 14 Reported Survivals Following Coronary Artery Bypass by Author, by Year, and by Duration Survival (%) Reference (yr)

Age (yr)

1 yr

36 36 69 <70 >70 >70 >80 >80 >80 >80 82

— 98 93 98 91 92 89 90 87 87 —

113 (1994) 126 (1995) 127 (1985) 90 (2002) 121 (1988) 90 (2002) 117 (1994) 118 (1990) 128 (1997) 90 (2002) 110 (1992)

3 yr — 93 90 95 88 88 77 76 78 77 77.4

5 yr

6–7 yr

86 90 83 92 86 82 66 60 66 73 —

— 85 80 85 — — — 47 —

Table 15 Reported Survivals Following Coronary Artery Bypass by Author, by Gender, and by Duration Survival (%) Reference (yr)

Age (yr)

1 yr

3 yr

5 yr

6–7 yr

10 yr

15 yr

Men

45 46–54 55–64 65–74
75

92 94 90 83 69

82 86 75 60 40

64 72 55 35

Women

45 46–54 55–64 65–74
75

96 98 87 84 77

85 81 71 70 38

81 67 55 35 28

116 (1993)

of treatment of their CAD. However, their survival is better with CABG than it is with either PTCA or medical management (89,130–134) (Table 16). Table 17 summarizes survival data following PTCA (87,88,117,131,135). Immediate mortality following PTCA in the elderly is consistently lower than that following CABG. In controlled studies, five-year survival following PTCA closely approximates that following CABG (except for therapeutic drug monitoring) (88,89,135). Table 18 compares long-term survival following medical treatment of CAD with that following CABG in the elderly (110,127). Although it is probable that, in these nonrandomized studies, patients treated medically were sicker than those treated surgically, the data that are available strongly suggest that elderly patients who undergo CABG fare better than their medical counterparts in terms of prolonged survival, relief of symptoms, and restoration of an active lifestyle. Cumulative six-year survivals of 1491 patients aged 65 years or older in the Coronary Artery Surgery Study (CASS) were 80% in the surgical group and 63% in the medical group (127). Ko et al. (110) reported in 1992

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Table 16 Reported Survivals of Diabetes with CAD by Author, by Year, and by Duration (Various Modes of Therapy) Survival (%) Reference (yr)

Mean age (yr)

130 (1994)

68

132 (1991)

82

133 (1993)

59

134 (1991)

55

89 (1997)

62

131 (1996)

57 60

Study DM DM ND DM ND DM ND DM TDM TDM ND DM

þ þ þ þ þ þ þ þ þ þ þ þ

CABG MED CABG CABG CABG CABG CABG CABG CABG PTCA PTCA PTCA

1 yr

88 65

3 yr

95 92

83 — 98 96 93 88

97 93

95 90

5 yr

7 yr

72 50 64 — 96 89 91 85 81 66 92 82

94 81 86 74

10 yr

15 yr

48 24

24 18

76 63

64 41

87 74

Abbreviations: ND, nondiabetic; DM, diabetic; TDM, diabetic patients requiring insulin or oral hypoglycemic agents; þCABG, treated by coronary artery bypass; þPTCA, treated by balloon angioplasty.

Table 17 Reported Survivals Following PTCA or CABG by Author, by Year, by Duration, and by Treatment Survival (%) Reference (yr) 131 (1996) 87 (1994) 88 (1996) 89 (1997) 135 (1994) 117 (1994)

Mean age (yr)

Study

1 yr

3 yr

5 yr

7 yr

9–10 yr

57 60 62 61 62 61 62

ND þ PTCA DM þ PTCA PTCA CABG PTCA CABG ND* þ PTCA ND* þ CABG PTCA CABG PTCA

97.9 92.8 96.5 97.9 96.5 96.5

95.0 89.5 92.9 93.8 91.8 93.8

91.6 81.5

86.6 74.1

82.3 64.1

87.5 85.0 88.0 89.0

77.5 72.5 83.0 77.0

75 75 84 82

86.3 89.3 90.5 89.7 63.0 65.0 55.0 66.0

21.0 42.0

Abbreviations: ND, nondiabetic; PTCA, percutaneous transluminal coronary angioplasty; CABG, coronary artery bypass graft; ND*, nondiabetic and diabetics not requiring insulin or oral hypoglycemic agents.

that octogenarians treated by CABG had a better three-year survival than those treated medically (77.2% vs. 55.2%). Peterson (107), describing Medicare data, noted that oneyear survival was 92.1% after CABG in 147,822 individuals, 65 to 70 years old. Threeyear survival was 86.9%. One- and three-year survivals were 80.9% and 71.2% in 24,461 patients aged 80 years and older. Graham (90), reviewing data from the Alberta, Canada registry, reported that patients in three age groups had better four-year survival following CABG than they did following medical management (Table 19). In that study, those over 80 years of age benefited most from CABG. Procedural mortality was not reported.

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Table 18 Reported Survivals Following CABG or Medical Management by Author, by Year, by Duration, and by Treatment Survival (%) Reference (yr)

Age (yr)

127 (1985)


65 65–69 70–74
75
65 65–69 70–74
75 81 83

110 (1992)

Study

1yr

3 yr

5 yr

6 yr

CABG

93

90

83

MED MANAG

89

78

68

80 81 77 75 63 67 51 56

CABG MED MANAG

77 55

Abbreviations: CABG, coronary artery bypass graft; MED MANAG, medical management.

Table 19 Survival After Coronary Revascularization (APPROACH Data According to Ages and Treatment Modality) Percentage survival at 4 yr by treatment modality Age group (yr)

Number of patients

CABG

PCI

MED MANAG

15,392 5198 983

95.0 87.3 77.4

93.8 83.9 71.6

90.8 79.1 60.3

<70 70–79
80

Abbreviations: APPROACH, Alberta Provincial Project for Outcomes in Coronary Heart Disease; CABG, coronary artery bypass graft; PCI, percutaneous coronary intervention. Source: From Ref. 90.

Quality of Life As survival following treatment of ischemic heart disease has improved, measurement of the quality of the patient’s life following treatment has become a focus of increasing discussion. Evaluation of OM, morbidity, and survival are readily addressed by objective measurements, but quality of life is less easily measured objectively. Investigators often use indirect measurements such as freedom from cardiac events, relief of pain, decreased requirements for medication, or fewer hospitalizations as evidence of a better quality of life. Attempts to develop objective direct measurements have involved use of instruments such as the Duke activity score index, the SF 36 health survey, the Rose questionnaire for angina, the Hospital Anxiety and Depression scale, the Nottingham Health Profile, the EuroQuol Questionnaire, and changes in the NYHA or the Canadian Cardiac Society classification (136–138). Each requires patient’s self-assessment as well as the patient’s understanding of the questions, ability, and willingness to respond. Nevertheless, there is substantial data to indicate that both medical and surgical treatment improve the quality of patients’ lives. Freedom from Events Multiple authors have reported that at five years, 59–78% of elderly patients surviving CABG; 40–70% of those surviving PTCA; and 67% of those treated medically for CAD

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were free of recurrent cardiac events (128,135,139,140). The term “cardiac events” usually included death or new Q-wave infarction, but in some publications it also included reoperation, arrhythmia, and stroke. Freedom from Angina Severe intractable angina is the most frequent indication for CABG in the elderly. After CABG, 62–94% of patients were found to be free of angina with follow-up ranging from three months to eight years (12,110,118,122,127,135,140,141). Fifty-five percent to 82% of elderly patients treated by PTCA and 29–51% of those treated medically were free of angina (12,87,118,127,135,140,142). Vogt (142) reported that 85% of elderly patients treated by CABG were free of angina 6 to 12 months later compared with 55% of those treated by PTCA and 51% of those managed medically. In general, PTCA and medically treated patients were more likely to be taking antianginal medications than were the CABG patients. The advantages of surgical treatment over medical treatment seem to decrease slowly over time but were sustained for at least 10 years (141). Posttreatment MI The frequency of recurrent or late MI one to five years after CABG in the elderly ranged from 0% to 2%. Following PTCA, the frequency was 2–6%. After medical management, the frequency of a new MI was as high as 28% (122,135,143). Functional Status In terms of mobility, ability to care for themselves or live independently, the elderly clearly benefit more from CABG than from medical management. When the high frequency of CABG following PTCA is considered, patients treated only by CABG probably have a better quality of life than do those treated only by PTCA. Ko (110) reported that CABG produced a significant improvement in functional capacity lowering the NYHA classification from an average of 3.4 preoperatively to 1.2 postoperatively. Medical management did not (2.8 to 2.5). Similarly, Mullany (118) found that 89% of the elderly undergoing CABG were returned to NYHA class I or II. Preoperatively, 97% of the patients were NYHA class III or IV. Krumholz (143), evaluating 93 octogenarians following hospitalization for an acute MI, found that one year later, 89% of those treated by CABG, 86% of those treated by PTCA, and 44% of those treated medically rated their quality of life as good or excellent. King (87) reported that 44.5% of patients treated by CABG and 47% of those treated by PTCA were able to engage in moderate or strenuous activity. Akins (128) commented that 86% of octogenarians who had undergone CABG were living at home or with their families. Krumholz et al. (143) found that 89% of octogenarians treated by CABG, 89% of those undergoing PTCA, and 55% of those treated medically for CAD were living independently. For comparison, earlier in this chapter the comment was made that half of the general population 85 years or older still lived alone or with their spouses (21). Several authors have attempted to measure quality of life objectively. Vogt (142), measuring outcomes in 98 individuals older than 70 years, found that patients undergoing CABG were significantly more able to engage in the basic and intermediate activities of daily living than were those who underwent PTCA or medical therapy. Hlatky et al. (12) measured functional status following CABG or PTCA in a group of 934 patients with a mean age of 62 years. Employing the Duke Activity Status Index, he reported that

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improvement was significantly better after CABG than after PTCA (7.0 vs. 4.4). Chocron et al. (141), using the Nottingham Health Profile, found that three months after CABG, 92% of elderly patients reported improvement in their social activities, 89% in their energy, 80% in their physical mobility, and 79% in their pain. Speziale et al. (144), using a questionnaire that evaluated five areas of activity, reported the results at three years from 203 patients treated by CABG, 107 patients treated medically, and 107 normal patients. Mean age was 60 years. The surgical patients scored significantly better than the medical patients, but both treatment groups scored significantly worse than the normals.

COSTS From the data presented, it is apparent that CABG and/or PTCA cannot only extend the life of elderly patients with CAD, but also they can prevent further myocardial injury, restore function, and increase the quality of life. Costs, however, are a valid consideration as these procedures are performed in increasing numbers of the elderly. Peterson et al. (107) noted that the rate of CABGs performed in those aged 65 to 70 grew from 38.1/10,000/yr in 1987 to 42.1/10,000/yr in 1990. The rate in octogenarians grew from 7.2/10,000/yr in 1987 to 12.0/10,000/yr in 1990. The total number of bypass operations performed in octogenarians is expected to increase from 8000 in 1990 to more than 30,000 by 2050 at an in-hospital cost that will exceed $1.2 billion in 1990. In 1990, the mean hospital cost for a CABG performed in patients 65 to 70 years old was $21,700; for those in their 80s the mean cost was $27,200 (107). The increased costs for CABG in the elderly result primarily from longer hospital stays and more intensive treatment rather than from the procedure itself. In turn, the prolonged stays are due to the presence and severity of coexisting disease, the generally more advanced stage of CAD at the time of operation, and the increased frequency of postoperative complications in the elderly. Smith et al. (145), reviewing economic outcomes in 1114 patients undergoing CABG, found that lower ejection fractions, higher age, CHF, presence of unstable angina, cardiomegaly, stroke, renal disease, and diabetes requiring insulin were significant patient factors that predicted higher costs. Lower age, higher ejection fractions, absence of diabetes, no prior PTCA, and male sex predicted earlier hospital discharge. Comparative costs of PTCA and CABG are also valid considerations. It is generally accepted that the initial costs for PTCA are significantly less than the costs of CABG (35– 84% less) (12). Over a period of time, however, the total cost of PTCA approaches that of CABG because of more frequent hospitalizations, more frequent revascularization procedures, and a greater cost for medications. Hlatky (12) concluded that over a three- to five-year period, balloon angioplasty has a significant cost advantage over CABG in patients with two-vessel disease. In patients with three-vessel disease, the costs were similar. In diabetics with CAD, bypass surgery was more cost-effective than angioplasty. As the number of cardiac revascularization procedures performed in progressively older patients continues to increase and the cost of health care continues to escalate, the question of cost-effectiveness of these procedures in the elderly has become a topic of discussion among health planners. The TIME investigators (Switzerland) (136) noted that individuals older than 75 years represent the fastest growing segment of the population. They pointed out that more than one-third of the total health care expenditures are consumed by this group of individuals in whom coronary artery disease is the most prominent cause of morbidity and mortality. Sollano (138) studied the cost-effectiveness of CABG surgery versus medical management in 224 patients 80 years of age or older.

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Survival and quality of life were evaluated posttreatment. Cost per quality-adjusted lifeyears saved was calculated. In the group undergoing CABG the cost per year was $10,424, well within the benchmark of $50,000 per year considered to be cost-effective for a number of other treatments. They concluded that performance of CABG surgery in octogenarians was highly cost-effective. RECENT DATA The Society of Thoracic Surgeons National Database reviewed retrospectively 662,033 patients (five patients older than 100 years old, 1092 patients aged 90 to 99 years, 59,576 patients aged 80 to 89 years, and 621,360 patients aged 50 to 79 years) who underwent cardiac surgical procedures from 1997 through 2000 (146). For CABG patients, OM was 11.8% for patients aged 90 years and older, 7.1% for patients aged 80 to 89 years, and 2.8% for patients aged 50 to 79 years. Patients aged 90 years and older, who did not have emergent/salvage CABG, preoperative intra-aortic balloon, renal failure, peripheral vascular disease, or cerebrovascular disease had an OM of 7.2% (146). In 500 consecutive patients aged 80 to 94 years who had CABG, revasculaization was complete in 400 patients (80%) (147). OM was 7% in the 400 patients with complete revascularization and 13% in the 100 patients with incomplete revascularization. Excluding operative deaths, the mean survival was 82 months in patients with complete revascularization versus 65 months in patients with incomplete revascularization. The five-year survival was 62% in patients with complete revascularization versus 45% in patients with incomplete revascularization. The eight-year survival was 39% in patients with complete revascularization versus 25% in patients with incomplete revascularization (147). A propensity analysis of long-term survival after CABG or PTCA in 6033 consecutive patients, mean age 65 years, with multivessel CAD and high-risk features showed that PTCA was associated with an increased risk of death (propensity-adjusted hazard ratio ¼ 2.3) (148). This difference was observed across all categories of propensity for PTCA and in patients with DM or left ventricular dysfunction (148). Cardiac rehabilitation programs can be used to optimize the recovery outcomes of elderly persons after CABG (149). Octogenarians undergoing CABG have better health status at four years than those in the same age group who did not undergo revascularization (150). Octogenarians with preoperative comorbidities such as DM, CHF, stroke, hypertension, carotid artery disease, and low left ventricular ejection fraction have an excellent quality of life after CABG (151). In 4739 patients, mean age 67 years, undergoing CABG, multivariate analysis showed that preoperative use of lipid-lowering therapy reduced in-hospital mortality by 17% (153). In elderly high-risk patients, no significant difference was found in the incidence of cognitive dysfunction at three months with either off-pump CABG or with conventional CABG (152). INDICATIONS FOR CABG IN THE ELDERLY Compared with cardiac disease in the younger population, CAD in the elderly is more likely to be associated with severe complications and a higher mortality from those complications. Age, in itself, has been shown repeatedly to be an independent predictor of an increased OM. Thus, the elderly face greater risks in the perioperative period while at the same time the durability of long-term benefits is necessarily limited. Nevertheless,

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conclusions drawn from the randomized studies together with data from multiple nonrandomized studies of coronary revascularization in the elderly have led to generally accepted indications for CABG in older patients. As summarized by Aronow (154), they are as follows: 1. Significant left main disease 2. Significant three-vessel disease, especially in the presence of a decreased left ventricular ejection fraction and ischemia 3. Significant two- or three-vessel disease, a decreased left ventricular ejection fraction, and significant stenosis of the proximal left anterior descending coronary artery 4. ST-segment depression on resting ECG plus at least two of the following— NYHA functional class III or IV, history of MI, history of hypertension, or all three without ECG changes 5. Significant two- or three-vessel disease and exercise-induced ischemic ST-segment depression of 1.5 mm or greater 6. Clinical evidence of CHF during ischemic episodes with ischemic but viable myocardium 7. Unacceptable symptoms despite optimal medical management. Rihal et al. (155) performed a meta-analysis of trials comparing PTCA with CABG. These investigators found that is preferred for high-risk patients such as those with left main CAD, severe three-vessel CAD, diffuse CAD, severe left ventricular dysfunction, or DM. Both PTCA and CABG provided good symptom relief. However, repeat procedures are required more frequently after PTCA than after CABG (154). SUMMARY Coronary angioplasty or bypass is being performed for increasing numbers of patients in their seventh, eighth, ninth, and even tenth decades of life. Both silent and overt CAD are more common in the population over 65. Because CAD in the elderly presents more often in an atypical manner, diagnosis of the disease is frequently delayed. As a result, the elderly typically face the operation with a higher prevalence of complications of their CAD. MI, impaired myocardial function, and CHF are more frequent in the elderly. CABGs are performed more frequently as emergencies in older individuals, particularly those aged 80 years or older. Nevertheless, it is clear from recent reports that elective CABG can be performed with operative mortalities in the 1.0–4.0% range even in 70- and 80-year-olds. Survival of the elderly treated by CABG approximates that of a general population of the same age group and is markedly superior to that achieved by medical management. It is also true that CABG in older individuals improves the quality of life over and above that observed following alternative methods of treatment, particularly medical management. While the costs of performing CABG in the elderly are higher than they would be for a younger population, it is not clear that these costs are higher in the long run than they would be for nonoperative treatment with its associated costs of repeated interventions and hospitalizations. Greater efforts directed toward detection of ischemic heart disease in the older population and performance of earlier, elective surgery could significantly reduce both the mortality and disability associated with CAD in the elderly. Delay in operation until the patient has a complication of CAD, particularly a MI, has a markedly adverse outcome in both the short and the long term.

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47. White PD, Bland EF. A further report on the prognosis of angina pectoris and of coronary thrombosis. A study of five hundred cases of the former condition and of two hundred cases of the latter. Am Heart J 1931; 7:1–14. 48. White PD, Bland EF, Miskall EW. The prognosis of angina pectoris. A long time follow-up of 497 cases, including a note on 75 additional cases of angina pectoris decubitus. J Am Med Assoc 1943; 123:801–804. 49. Reeves TJ, Oberman A, Jones WB, et al. Natural history of angina pectoris. Am J Cardiol 1974; 33:423–430. 50. Block WJ Jr., Crumpacker EL, Dry TJ, et al. Prognosis of angina pectoris. Observations in 6,882 cases. J Am Med Assoc 1952; 150:259–264. 51. Oberman A, Jones WB, Riley CP, et al. Natural history of coronary artery disease. Bull N Y Acad Med 1972; 48:1109–1125. 52. Proudfit WJ, Bruschke AVG, MacMillan JP, et al. Fifteen year survival study of patients with obstructive coronary artery disease. Circulation 1983; 68:986–997. 53. Pinsky JL, Jette AM, Branch LG, et al. The Framingham disability study: relationship of various coronary heart disease manifestations to disability in older persons living in the community. Am J Public Health 1990; 80:1363–1367. 54. Franc¸ois-Franck CA. Signification physiologique de la resection du sympathique dans la maladie de Basedow, 1’epilepsie, 1’idiotie et le glaucome. Bull Acad Med Paris 1899; 41:565–594. 55. Jonnesco T. Traitment chirurgical de 1’angine de poitrine par la resection du sympathique cervico-thoracique. Bull Acad Med Paris 1920; 84:93–102. 56. Lindskog GE, Liebow AA, Glenn WWL. Coronary heart disease. In: Lindskog GE, Liebow AA, Glenn WWL, eds. Thoracic and Cardiovascular Surgery with Related Pathology. New York: Appelton-Century-Crofts, 1962:871–879. 57. Urschel HC Jr., Razzuk MA. Surgery for coronary artery disease. In: Norman JC, ed. Cardiac Surgery. 2nd ed. New York: Appelton-Century-Crofts, 1972:447–472. 58. Cutler EC. The surgery of the heart and pericardium. In: Walters W, ed. Lewis’ Practice of Surgery. Hagerstown: WF Prior Co., 1948:46–59. 59. Beck CS. The development of a new blood supply to the heart by operation. Ann Surg 1935; 102:801–813. 60. Beck CS, Leighninger DS. Coronary heart disease treated by operation. Arch Surg 1962; 85:383–389. 61. Vineberg AM. Development of anastomosis between coronary vessels and transplanted internal mammary artery. Can Med Assoc J 1946; 55:117–119. 62. d’Abreu AL, Clarke DB. The history of cardiac surgery. In: Norman JC, ed. Cardiac Surgery. 2nd ed. New York: Appelton-Century-Crofts, 1972:3–12. 63. Mueller RL, Rosengart TK, Isom OW. The history of surgery for ischemic heart disease. Ann Thorac Surg 1997; 63:869–878. 64. Culverwell M. Portrait: Rene Favaloro, Pan-American pioneer of bypass. Cardiology 1985; 2:46–47. 65. Johnson WB, Flemma RJ, Lepley D Jr., et al. Extended treatment of severe coronary artery disease: a total surgical approach. Ann Surg 1969; 170:460–470. 66. Urschel HC Jr., Miller ER, Razzuk MA. Aorta-to-coronary artery vein bypass graft for coronary artery occlusive disease. Ann Thorac Surg 1969; 8:114–120. 67. Kerth WJ. Aorta-coronary bypass grafts. J Thorac Cardiovasc Surg 1969; 57:487–192. 68. Matthews FP. Medicine. In: Paradise J, Waxman ML, Shores L, eds. 1968 Yearbook. New York: Crowell-Collier Educational Corp., 1968:350–354. 69. Rutkow IM. Surgical operations in the United States. Then (1983) and now (1994). Arch Surg 1997; 132:983–990. 70. Bhayana JN, Gage AA, Takaro T. Long-term results of internal mammary artery implantation for coronary artery disease: a controlled trial. Ann Thorac Surg 1980; 29:234–241. 71. The Veterans Administration Coronary Artery Bypass Surgery Cooperative Study Group Eleven-year survival in the Veterans Administration randomized trial of coronary bypass surgery for stable angina. N Engl J Med 1984; 311:1333–1339.

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91. Erikssen J, Thaulow E. Follow-up of patients with asymptomatic myocardial ischemia. In: Rutishauser K, Raskamm H, eds. Silent Myocardial Ischemia. Berlin: Springer-Verlag, 1984: 156–164. 92. Parmley WW. Silent ischemia. In: Chatterjee K, Karliner J, Rapaport E, et al., eds. Cardiology: An Illustrated Text/Reference. Cardiovascular Disease, Vol 2. Philadelphia: Lippincott, 1991:7.91–7.99. 93. Cohn PF. Silent ischemia. Heart Dis Stroke 1992; 1:295–297. 94. Diamond GA, Forrester JS. Analysis of probability as an aid in the clinical diagnosis of coronary-artery disease. N Engl J Med 1979; 300:1350–1358. 95. Aronow WS, Ahn C, Mercando AD, et al. Prognostic significance of silent ischemia in elderly patients with peripheral arterial disease with and without previous myocardial infarction. Am J Cardiol 1992; 69:137–139. 96. Kannel WB. Silent myocardial ischemia and infarction: insights from the Framingham study. Cardiol Clin 1986; 4:583–591. 97. Aronow WS. Clinical characteristics of coronary artery disease in the older patient. Clin Geriatr 1993; 1:6–12. 98. Bayer AJ, Cadha JS, Farag RR, et al. Changing presentation of myocardial infarction with increasing old age. J Am Geriatr Soc 1986; 34:263–266. 99. Wroblewski M, Mikulowski P, Steen B. Symptoms of myocardial infarction in old age: clinical case, retrospective and prospective studies. Age Ageing 1986; 15:99–104. 100. Dunn FG. Coronary heart disease and acute myocardial infarction. In: Messerli FH, ed. Cardiovascular Disease in the Elderly. Boston: Martinus Nijhoff, 1984:149–169. 101. Kannel WB, Belanger AJ. Epidemiology of heart failure. Am Heart J 1991; 121:951–957. 102. Kannel WB, Thomas HE Jr. Sudden coronary death: the Framingham Study. In: Greenberg HM, Dwyer EM, eds. Sudden Coronary Death. New York: The New York Academy of Sciences, 1982:3–21. 103. Kannel WB, Schatzkin A. Sudden death: lessons from subsets in population studies. J Am Coll Cardiol 1985; 5:141B–149B. 104. Weintraub WS, Craver JM, Cohen CL, et al. Influence of age on results of coronary artery surgery. Circulation 1991; 84(suppl 3):III226–III235. 105. Edwards FH, Grover FL, Shroyer ALW, et al. The Society of Thoracic Surgeons National Cardiac Surgery Database: current risk assessment. Ann Thorac Surg 1997; 63:903–908. 106. Curtis JJ, Walls JT, Boley TM, et al. Coronary revascularization in the elderly: determinants of operative mortality. Ann Thorac Surg 1994; 58:1069–1072. 107. Peterson ED, Cowper PA, Jollis JG, et al. Outcomes of coronary artery bypass graft surgery in 24,461 patients aged 80 years or older. Circulation 1995; 92(suppl 2):II85–II91. 108. Katz NM, Chase GA. Risks of cardiac operations for elderly patients: reduction of the risk factors. Ann Thorac Surg 1997; 63:1309–1314. 109. Edmunds LH Jr., Stephenson LW, Edie RN, et al. Open-heart surgery in octogenarians. N Engl J Med 1988; 319:131–136. 110. Ko W, Gold JP, Lazzaro R, et al. Survival analysis of octogenarian patients with coronary artery disease managed by elective coronary artery bypass surgery versus conventional medical treatment. Circulation 1992; 86(suppl 2):II191–II197. 111. He GW, Acuff TE, Ryan WH, et al. Risk factors for operative mortality in elderly patients undergoing internal mammary artery grafting. Ann Thorac Surg 1994; 57:1453–1461. 112. Dziuban SW Jr. Using information from databases to improve clinical practice: lessons learned under fire. Ann Thorac Surg 1997; 64:564–567. 113. Ott RA, Gutfmger DE, Miller MP, et al. Rapid recovery after coronary artery bypass grafting: is the elderly patient eligible? Ann Thorac Surg 1997; 3:634–639. 114. Carson JL, Scholz PM, Chen AY, et al. Diabetes mellitus increase short term mortality and morbidity in patients undergoing coronary artery bypass graft surgery. J Am Coll Cardiol 2002; 40:418–423. 115. Hirsch CH. When your patient needs surgery: weighing risks versus benefits. Geriatrics 1995; 50:26–31.

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116. Rahimtoola SH, Bennett AJ, Grunkemeier GL, et al. Survival at 15 to 18 years after coronary bypass surgery for angina in women. Circulation 1993; 88(pt 2):II71–II78. 117. Kaul TK, Fields BL, Wyatt DA, et al. Angioplasty versus coronary artery bypass in octogenarians. Ann Thorac Surg 1994; 58:1419–1426. 118. Mullany CJ, Darling GE, Pluth JR, et al. Early and late results after isolated coronary artery bypass surgery in 159 patients aged 80 years and older. Circulation 1990; 82(suppl 4):IV229–IV236. 119. Metzger JP, Tabone X, Georges JL, et al. Coronary angioplasty in patients 75 years and older; comparison with coronary bypass surgery. Eur Heart J 1994; 15:213–217. 120. Gehlot AS, Santamaria JD, White AL, et al. Current status of coronary artery bypass grafting in patients 70 years of age and older. Aust N Z J Surg 1995; 65:177–181. 121. Acinapura AJ, Rose DM, Cunningham JN Jr., et al. Coronary artery bypass in septuagenarians. Analysis of mortality and morbidity. Circulation 1988; 78(suppl 1):I179–IM84. 122. Hochberg MS, Levine FH, Daggett WM, et al. Isolated coronary artery bypass grafting in patients seventy years of age and older. J Thorac Cardiovasc Surg 1982; 84:219–223. 123. Yashar JJ, Yashar AG, Torres D, et al. Favorable results of coronary artery bypass and/or valve replacement in octogenarians. Cardiovasc Surg 1993; 1:68–71. 124. Zehr KJ, Lee PC, Poston RS, et al. Two decades of coronary artery bypass graft surgery in young adults. Circulation 1994; 90(suppl 2):II133–II139. 125. Tsai TP, Chaux A, Matloff JM, et al. Ten-year experience of cardiac surgery in patients aged 80 years and over. Ann Thorac Surg 1994; 58:445–451. 126. French JK, Scott DS, Whitlock RML, et al. Late outcome after coronary artery bypass graft surgery in patients <40 years old. Circulation 1995; 92(suppl 2):II14–II19. 127. Gersch BJ, Kronmal RA, Schaff HV, et al. Comparison of coronary artery bypass surgery and medical therapy in patients 65 years of age or older. A nonrandomized study from the Coronary Artery Surgery Study (CASS) registry. N Engl J Med 1985; 313:217–224. 128. Akins CW, Daggett WM, Vlahakes GJ, et al. Cardiac operations in patients 80 years old and older. Ann Thorac Surg 1997; 64:606–615. 129. Gersh BJ. LV ejection fraction vital for elderly bypass patients. Cardiol Times 1983; 2:31. 130. Barzilay JI, Kronmal RA, Bittner V, et al. Coronary artery disease and coronary artery bypass grafting in diabetic patients aged
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Percutaneous Coronary Intervention in the Elderly David R. Holmes Jr. and Mandeep Singh Mayo Clinic College of Medicine, Mayo Clinic, Rochester, Minnesota, U.S.A.

The numbers of older (age over 65 years) and oldest (those over age 80 years) patients with coronary artery disease (CAD) are increasing in our society at a tremendous rate. Indeed, there has been unsurpassed growth in the elderly population in the last 10 to 15 years. Within a decade, one-sixth of the population, representing 45 million people, will be over the age of 65 (1), with half of those being over the age 75 and some 25% of those over the age of 80. The elderly have a high prevalence (about 60%) of significant atherosclerotic CAD in at least one coronary vessel, with many becoming symptomatic enough to require definitive treatment (2). The increase in prevalence of CAD with increasing age is seen irrespective of gender status (3). Patients older than 65 now constitute over half of all patients undergoing coronary revascularization procedures at major medical centers (4–7). Unfortunately, many studies of revascularization for symptomatic CAD in the past have either excluded patients over the age of 70 to 75 or have included insufficient number of patients to draw effective conclusions. There is a high proportion of more extensive disease, more frequent and more severe medical comorbidities, and poorer success rates leading to higher complication/death rates in the elderly, both with percutaneous coronary intervention (PCI) (7–9) as well as with coronary artery bypass surgery (CABG) (10). These factors make the decision to perform coronary revascularization challenging. With the rapid evolution of PCI techniques, one must continually reevaluate PCI’s applicability in the setting of older, sicker patients to better advise about its relative benefit versus alternative treatment strategies.

BASIS FOR INTERVENTION IN THE ELDERLY Recent studies have shown that elderly patients with symptomatic CAD have poorer longterm and event-free survival with medical therapy alone compared with revascularization (11,12). The large observational Alberta Provincial Project for Outcomes Assessment in Coronary Heart Disease (APPROACH) study, set in the mid-1990s, (6000 patients with

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CAD over age 70, about 1000 patients over age 80) noted age-related differences in adjusted four-year survival in the elderly with medical treatment (MED) compared with PCI and CABG as follows: aged below 70 years MED ¼ 90.5%, PCI ¼ 93.8%, CABG ¼ 95%; aged 70 to 79 years MED ¼ 79.1%, PCI ¼ 83.9%, CABG ¼ 87.3%; aged above 80 years MED ¼ 60.3%, PCI ¼ 71.6%, CABG ¼ 77.4% (11). Elderly patients, in general, did poorer with medical therapy, and this trend seemed to worsen with increasing patient age. Graham et al. and other study groups (11,13) have shown the benefits of revascularization in carefully selected elderly patients are more pronounced. In addition to frequent symptoms, some 50% of medically treated patients will be admitted with an acute coronary event, a trend that can be favorably impacted with timely revascularization therapy (12). Other factors in the elderly limit the overall utility of medications as a primary option for therapy; their ischemia is often refractory to medication, leading to the more frequent need to maximize medical therapy (14). Maximizing medical therapy with multiple medications can lead to multiple adverse drug-drug interactions. Elderly patients often have a substantial degree of medication intolerance (due to peptic ulcer disease/other gastrointestinal conditions among others), as well as cognitive impairment that can lead to poorer compliance with medications than younger patients (15–17). Undoubtedly, for a multitude of reasons, older patients tend to downplay their symptoms and delay seeking care; when they do present with active coronary ischemia, they are more likely to do so late, with signs of severe congestive heart failure (CHF), acute myocardial infarction, and/or cardiogenic shock (8,9). It is these very subsets of elderly who are shown to carry a poorer prognosis with medical therapy in the absence of revascularization (18,19). Together with a high prevalence of chronic symptomatic ischemia, a high burden of atherosclerosis, and many medical comorbidities, active CAD can be a tremendously disabling problem in the elderly, one that often prompts patients to consider the more definitive benefits offered by revascularization therapy. The Trial of Invasive versus Medical Therapy in Elderly Patients (TIME) (12) randomized 301 elderly patients aged 75 years and above to either coronary angiography and revascularization or to further optimization of medical therapy. At baseline, three quarters of the patients had Canadian Cardiac Society (CCS) class III or IV angina pectoris despite using an average of 2.5 antianginal drugs. The primary endpoint was quality of life assessed at six months. Although angina severity decreased and quality of life improved in both groups, these improvements were significantly greater in the group of patients treated with revascularization. In the invasive group, 19% had a major adverse cardiac event at six months versus 49% in the medical group ( p < 0.0001). The one-year follow up of the TIME trial in elderly patients has now been reported. Pfisterer et al. reported on 282 patients with CCS class II or higher angina who survived for the first six months after enrollment. The mean age was 80 years. At one year, there was no statistically significant difference in death [11.1% for invasive versus 8.1% for medical therapy; hazard ratio (HR) 1.51, 95%, confidence interval (CI) 0.72–3.16, p ¼ 0.28] or the combined endpoint of death or nonfatal infarction (17% for the invasive group vs. 19.6% for the medical therapy group, HR 0.90, 95%, CI 0.51–1.53, p ¼ 0.71). There was, however, a marked difference in subsequent revascularization. Patients randomized to medical therapy had a 46% chance of later hospitalization and revascularization versus 10% with an invasive approach (HR 0.17, 95%, CI 0.11–0.32, p < 0.001) (20). After four years, the patient survival was 70.6% in the invasive group versus 73% in the medically treated group (not significant). Survival rates were, however, better if patients were revascularized within the first year of study entry. At four years, freedom from major adverse cardiac event rate remained significantly higher in the invasive group (21).

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Quality of life has also been assessed after coronary revascularization in the elderly. Graham et al. (22) evaluated four-year health status in elderly patients using the Seattle Angina Questionnaire. At four years of follow-up, health status was better in patients who had undergone revascularization as the index procedure compared with medical therapy. Finally, cost effectiveness has also been studied in the setting of the TIME trial. Costs were determined by resource utilization at one year. The two strategies had different cost profiles, with invasively treated patients having higher initial costs, but medically treated patients having higher subsequent costs. Accordingly, at one year, patients treated with an invasive strategy had improved clinical outcomes at only marginally higher costs (23). CHARACTERISTICS OF THE ELDERLY PCI POPULATION Elderly subjects undergoing PCI are generally sicker than younger ones because of a higher prevalence of comorbid medical conditions (7,23,24). Patients over age 65 frequently have hypertension and diabetes leading to more advanced CAD, peripheral vascular disease, and cerebrovascular diseases (6,23,24). In addition, older patients have a greater burden of coronary atherosclerosis associated with a relatively frequent history of PCIs and/or CABG, prior myocardial infarction, and resultant lower ejection fraction (EF) (6,14,23,25,26). On the basis of a multicenter registry study, CHF is common in the elderly and comparatively rare in younger patients; only 4% of patients younger than 65 have had CHF versus some 9% over 65 years and 20% over age 75 (14). This is true of both systolic and diastolic heart failure. In addition, there is a higher percentage of women undergoing PCI over age 75 (40–50%) compared with those younger than 65 (21%), a factor that alone shows a trend toward higher need for subsequent revascularization procedures (24). The presence of many adverse risk predictors in the elderly has a major impact on the suitability of the coronary artery lesion for PCI and is inherent in their higher procedural risk. There is a high incidence of multivessel CAD in patients with lower EFs. One study noted that 50% of patients over the age of 75 versus 33% of younger patients have multivessel disease, with some 13% of those over age 80 having left main coronary disease (27). Thus, in the early balloon era, only 31% of patients in their 80s were considered suitable candidates for angioplasty because of diffuse extensive CAD (27,28). With the rise of improved PCI techniques such as stenting, interventions for many of these advanced “type C” lesions are now routine, but the modified American Heart Association (AHA)/American College of Cardiology (ACC) characteristics still predict poorer overall short-and long-term success in this setting (29). As a consequence of more extensive disease, elderly patients are often more unstable upon presentation for intervention than younger patients, not uncommonly having had prior silent infarctions (30). They have a higher frequency of class III/IV angina, which is present during intervention in as many as 70% of patients over 65 and in an even higher number of those over age 80, compared with less than 50% of younger patients (6,14,23–26,31). OUTCOMES OF BALLOON ANGIOPLASTY IN THE ELDERLY Initial results in elderly patients undergoing angioplasty in the early 1980s showed relatively low acute success rates, higher procedural complications, and higher mortality (14,23). The results have been age-dependent, with those over age 75 having poorer outcomes than younger patients (14,23–26,32,33). Elderly patients who underwent

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angioplasty at the Mayo Clinic between 1980 and 1989 showed procedural mortality of 1.2% for patients below age 75 but 6.7% for those over age 75 (6). This is in keeping with other large centers during the same period (34). In a large Medicare database of some 20,000 patients, Jollis et al. reported in-hospital mortality rates of 7% in patients over age 80 with angioplasty (35). With lower profile balloons, perfusion balloons, in-lab monitoring of anticoagulation status, increasing operator experience, and occasional use of bailout stenting, angioplasty success had significantly improved by the early 1990s to an acceptable level of 88% to 93% (34,36) in elderly patients with single-vessel disease, but was still lower in the oldest subjects. Compared with the 1980s, results of angioplasties performed at Mayo Clinic from 1990 to 1992 showed a 50% drop in hospital mortality to 0.8% in patients aged 65 to 74 years and to 3% in those over age 75 (36). The rate of complications had also fallen during this time period, with procedural infarction rates in those over age 65 falling to 2.2% (vs. 3.9%, previously) and emergency bypass rates of 0.65% (vs. 5.5%). More recently, Feldman et al. (37) evaluated the effect of age on outcome in the New York State Registry using data from 2000/2001. In this series, 10,964 patients had undergone emergency PCI and 71,176 patients elective PCI. Patients were divided into three age groups, below 60 years, 60 to 80 years, and above 80 years. In both elective and emergency PCI, elderly patients had more comorbidities. Age was strongly predictive of in-hospital mortality for both elective and emergency cases. In the elective cases, mortality was 0.1%, 0.4%, and 1.1%, respectively ( p < 0.05); in the emergency cases, mortality was 1.0%, 4.1%, and 11.5%, respectively ( p < 0.05). Other medical complications postprocedure have also been a particular concern in the elderly. After angioplasty, Maiello and colleagues (38) described a 1.1% rate of renal insufficiency and a 5.4% rate of need for transfusion in patients over 70. As a result, the elderly tend to have longer hospital stays, although this may be favorably altered by careful attention to the amount of contrast dye used, better preprocedural hydration, less aggressive anticoagulant dosing, and the use of smaller caliber catheters. Of interest, longer hospital stays are associated with higher mortality, presumably reflecting complications that necessitate an extended hospitalization. PREDICTORS OF POOR EARLY OUTCOME WITH ANGIOPLASTY IN THE ELDERLY The strongest predictor of hospital death in the elderly is the presence of extensive or multiple vessel coronary disease (39). Maiello and colleagues (40) showed a high success rate, approaching 100% in patients over the age of 75, in single vessel angioplasty versus a success rate in multiple vessel treatment of only 52%. The overall procedural success rate depends on the additive number of vessels treated. Calcified coronary artery lesions have definitely been predictors of failed angioplasty procedures in the past, and, even in contemporary practice with stenting, are associated with poorer long-term event-free survival (29,41), because of a higher subsequent need for repeat revascularization procedures. LONG-TERM OUTCOMES IN THE ELDERLY FOLLOWING ANGIOPLASTY The long-term results after a successful angioplasty in the elderly have shown consistent improvement over time. By the early 1990s, Buffet et al. (32) and Thompson et al. (6) had shown four-year survival of 83% and 86%, respectively. The overall long-term survival

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rates were not significantly different among those over and those under 75 years of age. However, there was less satisfactory event-free survival in patients over 75 years in these series (6,32) that was probably less because of restenosis than to progression of their underlying advanced atherosclerotic disease. Restenosis rates have been quite similar, in the 31% to 44% range, with angioplasty in patients over 80 years, patients between 65 and 79, and in younger patients (24,42–45). The strongest predictor of event-free survival in the elderly postangioplasty is the extent of CAD. DeJaegere et al. (46) reported an 81% event-free survival at four years postangioplasty in patients over age 70 with single-vessel disease versus 45% in patients with multivessel disease. The extent of disease was also a multivariate risk predictor in a prior review of the Mayo Clinic angioplasty experience in the elderly (39). Other predictors of long-term event-free survival were the left ventricular systolic function, the presence of unstable angina, and the number of noncardiac medical problems (35,36,39,43–47). Clearly, there is a wide variation in risk in angioplasty patients, especially in the elderly. The number of adverse risk factors present greatly impacts the long-term risk of death or myocardial infarction. In a Mayo Clinic series with stratification by the number of risk predictors, we noted that elderly patients undergoing angioplasty with three-vessel CAD, recent CHF, and two other concomitant medical problems had three-year survival rates free of myocardial infarction of only 66%, while in the absence of these factors, survival was 96% (39).

ELDERLY PATIENTS WITH MULTIVESSEL DISEASE: ANGIOPLASTY VERSUS SURGERY Some authors have suggested that the reduced event-free survival seen in the elderly may relate to the frequency of incomplete revascularization with angioplasty, but others believe, it indirectly reflects the greater extent of active coronary disease in this population (39,46,47) associated with more coronary risk factors. Nonetheless, the relative lack of complete and durable revascularization achieved with angioplasty for multivessel disease in the elderly is a prime reason why many elderly patients will ultimately require surgery (48). This was one of the major findings in the elderly subset of the largest randomized multivessel coronary angioplasty versus bypass study in the Bypass Angioplasty Revascularization Investigation (BARI) trial, which enrolled 1829 patients from 1988 to 1991 (49). No significant difference in 30-day mortality (1.7% in each) was noted in the 709 patients aged 65 to 80 years compared with younger patients who were randomized, although many patients with angioplasty required repeat revascularization and some ultimately had CABG. In all age groups, only the subset with diabetes showed higher mortality with angioplasty versus bypass surgery, and this is definitely a consideration in elderly patients undergoing angioplasty in lieu of CABG (50). The rate of strokes with CABG was significantly higher in the elderly than with angioplasty (49). Since the prohibitively high revascularization rates with angioplasty seen in the overall population in BARI (52% vs. 6% with CABG at five years), stenting has become the preferred therapy. Importantly, even in the present era, not all lesions are suitable for stenting, and some may still be better treated with balloon angioplasty; hence these results are still clinically relevant in as many as 25% to 30% of PCI involving the elderly, particularly in small vessels, branch vessels, or those with heavy calcification. The randomized Stent or Surgery (SOS) trial evaluated age-related outcomes in 988 patients treated with either CABG (n ¼ 500) or stent-assisted PCI (n ¼ 488) (51). The

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impact of age on outcome was studied in patients aged 65 years or below versus older patients. In the older patients who were randomized to PCI, 19.5% required repeat revascularization versus 3.4% of patients treated with CABG ( p < 0.001). In the older patients, one-year health status was assessed, which included physical limitations, frequency of angina, and quality of life, and the outcome was similar irrespective of whether the initial treatment was PCI or CABG (51). RESULTS OF CORONARY STENTING IN THE ELDERLY Coronary stenting has become the dominant revascularization mode in the elderly with one- and two-vessel disease and, occasionally, in those with three-vessel CAD felt to be too high risk for CABG. In the early stenting era, Yokoi et al. (52) reported initial successful stent results to be lower in those over 75 years compared with younger patients for the initial Palmaz–Schatz stent (86% vs. 95%), with associated higher hospital mortality (4.1% vs. 1.2%). By the mid 1990s, the procedural success rate with lower profile, more easily deliverable stents had improved to 90.8% and 90.2% in two series by Chevalier et al. and Batchelor et al. (53,54) of 142 and 7472 octogenarians, respectively, but with poorer results compared with younger patients’ success rates of 95.5%. Overall in-hospital mortality was still around 3.5%, and combined death/infarction and stroke risks were 5.2%; stenting was associated with better procedural success rates and lower need for repeat revascularization, but higher vascular complication rates (52). Procedural success with stenting has increased compared with results from the early series and now ranges between 90% and 97% at major medical centers (55–57). A recent National Heart, Lung, and Blood Institutes Dynamic Registry study of PCIs from 1997 to 1999 (58) compared 307 patients over 80 years of age (oldest), 1776 patients aged 65 to 79 years (older), and 2537 patients below 65 years (youngest). Successful procedural treatment of all lesions attempted was lower in those over versus those under age 80 (84% vs. 92–93%) despite similar IIb/IIIa platelet glycoprotein receptor inhibitor use (26% to 29%), similar stent rates (72% to 73%), and similar rates of rotational atherectomy (5.2% to 7.2%). Accounting for the lesser success in the oldest patients was a higher burden of coronary disease with more vessels (two or more in 15% vs. 9.4% vs. 9.4%), more lesions (2 or more in 39.1% vs. 34.2% vs. 29.0%), and more graft vessels (8.5% vs. 8.3% vs. 3.9%) treated compared with the two younger groups. Complication rates included higher stroke rates in those over age 80 (1.0% vs. 0.5% older vs. 0.2% younger), higher in-hospital mortality (4.6% vs. 2.2% vs. 0.6%) and more nonfatal myocardial infarctions (6.2% vs. 3.1% vs. 2.2%). One-year survival, although lower with increasing age, was identical to the age-expected mortality rates of the general population, suggesting that successful revascularization in the elderly is beneficial (58). LONG-TERM RESULTS OF STENTING IN THE ELDERLY The earliest study that included a large number of elderly patients undergoing stenting with first-generation stents reported increased angiographic restenosis rates in 137 patients aged 75 years and older compared with 2551 younger individuals (47% vs. 28%) (57). The presence of more advanced coronary disease in those over 75 years old versus those under 75 years old was evidenced by higher rates of stenting in multiple vessels (44% vs. 27%), left main (7.35% vs. 1.5%), ostial lesions (15.5% vs. 7%), and more frequent use of rotational atherectomy for debulking of calcified lesions in the elderly (notably, all factors in restenosis). Other studies by Chauhan et al. (55) in

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300 octogenarians, Abizaid et al. (56) in over 700 patients over age 70, and Alfonso et al. (59) in 378 patients over age 65 years have all shown similar clinical restenosis rates when compared with younger patients, but higher in-hospital mortality rates (1.3% to 3.0% in those over age 80 vs. 0.2% to 0.7% in younger patients), procedural infarction rates (7% to 10% vs. 2%), bleeding and vascular complications (5% vs. 1.0%), and subsequent one-year mortality (5% to 9% vs. 1% to 2%). Many studies with coronary interventions in the past have shown that late events are related mostly to repeat revascularization; despite similar restenosis rates, patients over 75 are less likely to undergo repeat revascularization, possibly because of less aggressive late treatment (60). Drug-eluting stents have come to dominate interventional cardiology on the basis of the results of multiple randomized clinical trials that document marked reduction in both angiographic and clinical restenosis compared with conventional bare metal stents. There is limited information on the effect of age on outcome in this setting. Vlaar et al. (61) analyzed 2453 patients undergoing drug-eluting stents at Mayo Clinic to evaluate the effect of age on outcomes. They classified patients into four different age groups: 50–59, 60–69, 70–79, and over 80 years old. Although procedural success was 97.5% in the latter group, this was still significantly less than in younger patients ( p ¼ 0.044). In-hospital mortality in patients aged over 80 years was 1.9% versus 0.9% in those patients 50 to 59 years. At 12 months of follow-up, target lesion revascularization rates were similar across the age groups at 4.8%, 5.6%, 4.3%, and 4.4% for the 50 to 59, 60 to 69, 70 to 79, and over 80 years age-groups, respectively. There were, however, significantly higher major adverse cardiac event rates at older ages, with rates of 7.5%, 8.9%, 11.0%, and 16.2%, respectively, for the four groups. Also, the mortality was higher in the octogenarians at 8.8% versus rates of 1.4%, 2.3%, and 4.7% in the three younger groups, respectively ( p  0.001). Despite this increase in overall mortality, the life expectancy of octogenarians undergoing drug-eluting stent treatment was similar to that of the general Minnesota population of the same age and gender (61). Hassani et al. (62) also evaluated the outcome of drug-eluting stents in patients aged 80 years or above compared with younger patients. There were 339 octogenarians and 2827 younger patients. As could be expected, octogenarians had more adverse characteristics including more chronic renal failure, CHF, more extensive CAD, and lower EF. Multivariate analysis identified age over 80 years at the index procedure, cardiogenic shock, Q-wave myocardial infarction, and length of hospital stay to be independent predictors of mortality.

PREDICTORS OF STENTING OUTCOME IN THE ELDERLY In a landmark study reflecting relatively current practice in PCI, Klein et al. (62) examined 8828 octogenarians undergoing intervention with predominant stenting (75%) in the 100,000 patient ACC-National Cardiovascular Data Registry from 1998 to 2000. The most important factor identified as a predictor of in-hospital death in the elderly was the presence of an acute myocardial infarction within six hours of PCI. For those over age 80, treated in a nonemergency fashion, the overall mortality was only 1.4% (vs. 13.8% for intervention in the setting of acute infarction), with low stroke rates (0.34%) and infrequent renal failure (1.5%), but with a notable degree of vascular complications (3.0%). The overall success rate was 93%, with slightly lower success in those with acute infarctions (91% vs. 94%). Other predictors of increased procedural mortality in octogenarians, if present (vs. if not present), included decreased EF, acute renal failure (29% vs. 3.2%), peripheral vascular disease with vascular complications (8.2% vs. 3.3%),

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Table 1 Factors Predicting Adverse Outcome and/or Mortality with Percutaneous Coronary Revascularization in the Elderly Baseline characteristics

Procedural issues

Age >80 Numerous comorbid illnesses Frail health Prior CABG Prior myocardial infarction Cardiogenic shock Acute myocardial infarction Chronic renal failure Peripheral vascular disease Congestive heart failure

Decreased EF Respiratory failure/intubation Multivessel disease Left main coronary disease Intracoronary thrombus Saphenous vein graft disease Acute renal failure post-PCI Q-wave infarction post-PCI Stroke post-PCI Vascular access complication

Abbreviations: CABG, coronary artery bypass surgery; PCI, percutaneous coronary intervention.

procedural Q-wave infarction (17.4% vs. 3.7%), and stroke (17% vs. 3.3%). Predictors of higher mortality were two to three times as frequent with acute myocardial infarction. Other studies have identified the presence of multivessel disease, CHF, left main disease, thrombus, vein graft treatment, cardiogenic shock, chronic renal failure, prior myocardial infarction, prior CABG as additive predictors of poor outcome of PCI in the elderly in the stent era (7,8). Factors associated with adverse procedural outcome with PCI are listed in Table 1. PCI FOR ACUTE INFARCTION IN THE ELDERLY The Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries-I (GUSTO-I) trial was one of the first to recognize the survival advantage of rapid restoration of normal levels of coronary blood flow in the infarct-related artery. Reperfusion therapy was introduced with thrombolytic agents, but it became apparent that in the elderly, particularly those over age 75, thrombolysis resulted in worrisome levels of disabling and/or fatal strokes, negating some of the survival benefits of opened coronary arteries (63,64). The risk appeared to be higher with tissue plasminogen activator therapy than with streptokinase, leading to preferential use of the latter in the elderly. As angioplasty, and later stenting techniques, became accepted therapy in chronic stable angina, their use as primary therapy in acute infarction in the elderly was tested in a number of small studies. Initial success rates varied widely and ranged between 61 and 92%, depending on age and the presence/absence of multivessel disease, left ventricular dysfunction, bleeding complications, and other comorbidites. ACUTE CORONARY SYNDROMES IN THE ELDERLY There has been great interest in acute coronary syndromes in the elderly. This relates to the frequent comorbidities in this group and the higher rates of adverse outcomes. ST-Elevation Myocardial Infarction Reperfusion therapy has become the standard of care in ST-elevation myocardial infarction (STEMI). In the past 10 years, changes in the approach to reperfusion have

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evolved substantially, driven in part by the increased incidence of fatal and/or disabling strokes after thrombolysis in the elderly, especially those older than 75 years. This has resulted in greater acceptance of an invasive approach. Gottlieb et al. (66) studied trends in the management of acute infarction in 1475 patients aged 75 years or above in Israel. Over the 10 years during 1992–2002, there was a significant increase in reperfusion therapy (from 27% to 48%), medical therapy including aspirin (from 53% to 88%), b blockers (from 18% to 65%), and angiotensin-converting enzyme inhibitors (from 26% to 63%). During the same decade, there was a 42% reduction in the 30-day mortality (from 27% to 16%, OR 0.57, 95% CI 0.36–0.93) and a 20% reduction in one-year mortality (from 37% to 29%). Marked regional differences in care have been documented in older patients. Ko et al. (67) compared procedural and medication use and 30-day risk standardized mortality in 38,886 American fee-for-service Medicare beneficiaries versus 5634 similarly aged Canadian patients and found significant differences. Overall, the use of invasive procedures was higher in the United States [38.5% vs. 16.8% ( p < 0.001)]. Despite this, the standardized 30-day mortality was not different. This finding has not been universal. Harpaz et al. (68) studied 1009 patients aged 76 years and above in all coronary care units in Israel. Those patients who underwent coronary angiography were on average 2.2 years younger; in addition, they had a higher systolic pressure, lower Killip class, and lesser prevalence of STEMI. Of the patients who underwent coronary angiography, 67% underwent revascularization either with PCI or with surgery. These authors also found that in patients who underwent angiography, both the crude mortality as well as the adjusted one-year mortality rates were less (21% vs. 37% p < 0.0001). There are several potential different reasons for the differences in outcome from PCI in the elderly with STEMI. Popitean et al. (69) evaluated the French regional survey data. They found that with increasing age, there are increased prehospital delays. In addition, once in hospital, the time to diagnosis has been found to be increased in elderly patients, in part because of atypical symptom presentations. The elderly also received less guideline-based medication regimens (70,71). These and other data have moved the practice of reperfusion in STEMI toward an invasive strategy. Sakai et al. (72) evaluated 1087 patients treated by primary angioplasty and subdivided them by age 75 years and older and those younger than 75 years. They found that the mortality in the older patients was higher (8.1% vs. 4.0% p ¼ 0.0057). Successful reperfusion was achieved in 91.6% and 92.9% of patients, respectively. When reperfusion was successful, cardiac mortality in older patients was not statistically significantly higher (4.6% vs. 2.8% p ¼ 0.14). Guagliumi et al. (73) analyzed the outcome of elderly patients in the Controlled Abcixamab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) trial of PCI. They found that one-year mortality increased for each decile of age. In those patients below 55 years, one-year mortality was 1.6% but increased to 11.1% for patients above 75 years ( p < 0.0001). In addition, elderly patients had increased rates of stroke and major bleeding. An early, randomized trial of reperfusion therapy for acute infarction specifically in the elderly was recently reported by de Boer et al. (74). This study of 87 patients over age 75 years randomized 46 patients to PCI versus 41 patients to streptokinase therapy. Of the 41 patients who actually received PCI (two had CABG, two received MED, one died preangiography), 90% had a successful result, with 51% receiving stents. The results were dramatic, with in-hospital mortality (7% vs. 20%), 30-day mortality rates (7% vs. 22%), 1-year mortality (13% vs. 41%), stroke risk (1% vs. 7%), and reinfarction rates (2% vs. 15%), all showing significant advantages of PCI over thrombolysis.

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Non--ST-Elevation Myocardial Infarction Elderly patients with non–ST-elevation myocardial infarction (NSTEMI) also have more adverse baseline clinical characteristics as is seen with patients with STEMI. They are also treated differently than younger patients. Yan et al. (75) stratified 4627 patients admitted with an acute coronary syndrome in the Canadian Acute Coronary Syndrome Registry into three groups (<65, 65–74, and 75 years of age). Across a broad spectrum, the elderly patients were at higher risk but were less likely to receive evidence-based medical therapy or to undergo revascularization. In another large survey in Europe, Rosengren et al. (76) analyzed 10,253 patients from 25 countries. There was a significant inverse association between age and the likelihood of presenting with a STEMI. As has been true in other studies, elderly patients were investigated less intensively and were more apt to be seen by a general medical physician rather than a cardiologist (76). Substantial international variability in the care of elderly patients with acute coronary syndrome has also been documented. Alexander et al. (77) used data from the Sibrafiban versus Aspirin to Yield Maximum Protection from Ischemic Heart Events Post-Acute Coronary Syndromes (SYMPHONY) trials. They contrasted 1794 patients 75 years of age or above versus 14,043 below 75 years . Elderly patients, overall, were at higher risk at the time of the index presentation and underwent catheterization less frequently than younger patients. Absolute catheterization rates varied from 27% to 77%. Revascularization rates also varied. Of interest, in this study performance of cardiac catheterization was not an independent predictor of 90-day death or the combined endpoint of death or myocardial infarction. Finally, Avezum et al. (78) evaluated age in the Global Registry of Acute Coronary Events (GRACE) registry of 24,165 acute coronary syndrome patients from 14 countries. The medical therapies of aspirin, b blockers, thrombolytic therapy, statins, and IIb/IIIa glycoprotein inhibitors were all used less frequently with increasing age. In addition, performance of coronary angiography and PCI was also less frequent in the older patients. ACUTE INTERVENTION IN CARDIOGENIC SHOCK COMPLICATING MYOCARDIAL INFARCTION IN THE ELDERLY The Should We Emergently Revascularize Occluded Coronaries for Cardiogenic Shock (SHOCK) trial suggested a survival advantage with rapid revascularization for younger patients with cardiogenic shock (79). Unfortunately, there was a trend toward poorer outcome in those over age 75 who were revascularized versus those receiving aggressive medical treatment, which included use of an intra-aortic balloon pump (75% vs. 53% 30-day mortality). A portion of this trial occurred during an era of lower stent use as well as lesser use of IIb/IIIa receptor inhibitors. More recent observational studies of acute intervention in the elderly for cardiogenic shock have suggested significant survival advantages with stenting. The large GRACE investigation of 583 patients (April 1999 to June 2001) shows overall mortality rates of 59%, with rates of only 35% in those treated with stenting (19). Two smaller studies have shown similar benefits, but have attributed much of the effect to synergy between use of stents and the use of the IIb/IIIa receptor inhibitor, abciximab. In 96 and 13 patients, respectively, Chan et al. (79) and Giri et al. (80) noted angiographic success rates (TIMI-3 flow) of 85% in the abciximab-stenting patients versus lower rates (64–67%) with stenting alone, angioplasty plus abciximab or angioplasty alone. Mortality in the abciximab-stenting groups was 13% to 22% (vs. 36–38% in both angioplasty groups and 36–52% mortality in the stent only groups), indicating significant benefit of stenting

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plus abcixamab in these high-risk patients. Prasad et al. (82) evaluated the outcome of elderly patients with shock at Mayo Clinic who underwent PCI. In 61 patients with a mean age of 79.5 years, in-hospital mortality occurred in 44%. However, the one-year survival after hospital discharge was 75%. Although the momentum is building toward a preferred role for acute interventions in elderly patients with acute cardiogenic shock, one must await randomized multicenter trials to make firm recommendations. In an elderly patient with minimal prior comorbidities, PCI with stenting in acute cardiogenic shock may be a consideration, whereas it may not be appropriate in a frail patient with numerous health concerns. MULTIVESSEL STENTING RESULTS IN THE ELDERLY With the advent of better stenting strategies, better techniques/devices to address higher risk ACC/AHA type C lesions, and the rise of antiplatelet therapies, outcomes with PCI have improved in general (83). Thus, PCI has become an attractive, if not preferred, alternative to bypass surgery, especially in candidates not favorable for or desiring CABG. The questions are whether it is appropriate to perform multivessel stenting in the elderly, and what are the benefits/problems in comparison to CABG? A number of contemporary trials of multivessel stenting compared with CABG for extensive disease have been reported. The largest trial, Arterial Revascularization Therapy Study (ARTS), randomly assigned 1205 patients (600 to PCI vs. 605 to CABG) (84). The results in the nondiabetics showed low one-year mortality in both assigned therapies (1.6% PCI vs. 2.8% CABG), with an overall 76% event-free survival at 18 months with stents compared with 88% with CABG ( p < 0.0001). Some 11.7% of PCI-assigned patients (vs. 2.9% CABG patients) required subsequent PCI while 3.9% later underwent CABG (vs. 0.6% CABG patients). Although CABG showed significantly better symptom-free survival, the stenting results were much more favorable than those at a similar follow-up stage in the BARI angioplasty subset (50), despite 70% of patients having complex type B2/C lesions. Results in the 208 randomized diabetic patients were not as attractive with PCI as with CABG (63% vs. 84% event-free survival at 18 months), possibly related to the low 3.5% rate of abciximab use in this high-risk subset. In contrast, it was possibly the 28% use of abciximab and the higher procedural CABG mortality (5.7% vs. 0.9%) that allowed multivessel stenting to show a better 18-month survival rate than CABG (96.9% vs. 92.5%; p < 0.02) in the Argentine Randomized Study: Coronary Angioplasty with Stenting versus Coronary Bypass Surgery in patients with Multiple-Vessel Disease(ERACI)-2 trial of multivessel therapy options (85). In the 225-patient PCI arm versus a similar-sized CABG arm, there was also a lower long-term rate of infarction (2.3% vs. 6.6%; p < 0.02), but the rate of repeat revascularization with PCI versus CABG patients was 16.8% compared with 4.8%. The randomized SOS trial, with 500 CABG patients and 488 multivessel PCI patients, also showed a high rate of two-year repeat procedures of 21% in the PCI group versus 6% in the CABG patients (51). The low surgical mortality rate of 2% was in keeping with some 50% of patients having stable angina; the mortality rate in patients with unstable angina in the ERACI trial was 7.9%. Perhaps one of the most relevant trials to date in the elderly and in high-risk patients was the recently reported Angina With Serious Operative Mortality Evaluation (AWESOME) trial. It enrolled 454 medically refractory veterans from 1995 to 2000 with one or more high-risk characteristics: age over 70 years, cardiac shock needing intraaortic balloon pumping, EF less than 35%, prior CABG, and recent infarction (86). With 222 patients receiving multivessel stenting and 232 receiving CABG—and at least 50%

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over age 67—it showed comparably low 30-day (5% vs. 3%), six-month (10% vs. 6%), and three-year mortalities (21% vs. 20%) with CABG versus PCI, respectively. Thus, elderly patients, who are at high risk due to one or more of the above risk factors, may be able to avoid the longer recovery of CABG and live just as long with multivessel stenting.

OPTIONS FOR REVASCULARIZATION IN THE ELDERLY From early revascularization era, a definite role for CABG has emerged in higher risk patient groups on the basis of its consistent beneficial effect on long-term survival and in reducing anginal symptoms (11,50,87–89). The success of CABG versus PCI in the elderly has been attributed mostly to CABG’s greater efficacy at achieving complete revascularization of all or most affected vessel territories in the setting of multivessel CAD, left main CAD, advanced AHA/ACC lesion class, and/or lower EF (9,43,51,82–91). Whereas balloon angioplasty in the 1980s and early 1990s was an accepted therapy for single-vessel disease (92,93), the frequent problem of restenosis, as demonstrated by five-year revascularization rates exceeding 50% in BARI, has limited its widespread application in multivessel diseases, particularly in the presence of diabetes (49,50). CABG has been utilized as a viable revascularization option in older patients with extensive CAD because past studies with PCI, even those with stenting, have shown frequent recurrent angina leading to repeat PCIs and ultimate need for CABG in up to 20% of patients (49–51,54–56,84,86). Unfortunately, CABG surgery in the elderly is not entirely a benign procedure. The overall mortality rate of CABG in a 1990 Medicare database of nearly 24,500 patients over age 80 was higher compared with patients aged 65 to 70, with poorer in-hospital mortality (11.5% vs. 4.4%), one-year mortality (19.3% vs. 7.9%), and three-year mortality (28.8% vs. 13.1%) rates (94). Many elderly patients are also at substantial risk of perioperative myocardial infarction, pneumonia, renal failure, prolonged mechanical ventilation, and neurological events, with rates between 2 and 10% (49,95). Given these risks, in addition to cognitive impairments seen in approximately 60% short term and approximately 20% long-term post-CABG in the elderly (95–97), many patients will not regain their previous level of function and, thus, suffer a loss in their quality of life. Some elderly patients, particularly those who have extensive CAD, a recent or prior myocardial infarction, prior revascularization, or additional comorbidities, will have even higher potential morbidity and mortality with CABG. The search for a viable alternative to CABG has continued to make steady progress. Recent PCI studies with predominant stent use demonstrate comparable or slightly better survival with PCI versus CABG but have still failed to avoid the subsequent need for additional revascularization in the PCI group, especially in the setting of diabetes (81–86). The question, when deciding upon the most suitable revascularization modality, is whether the higher procedural morbidity/mortality with CABG is justified by the 20% lower five-year need for repeat revascularization compared with PCI. In the setting of numerous comorbidities or frailty, elderly patients may be better served with moderateduration symptomatic improvement offered by PCI. Indeed, one issue many studies fail to recognize when reporting poorer long-term survival in the elderly after either CABG or PCI is that the long-term survival with a successful revascularization modality is not very different compared with others of similar age (8,94). Factors favoring preferential attempts at PCI with stenting compared with those favoring CABG in the elderly are listed in Table 2.

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Table 2 Factors Favoring Better Revascularization Results with Either Percutaneous Coronary Intervention or Coronary Artery Bypass Surgery in the Elderly Patient characteristics Percutaneous intervention better

Coronary bypass better

Age over 80 Numerous comorbid illnesses Frail health/limited life expectancy Major depression Poor motivation to rehabilitate Morbid obesity/severe COPD

Diabetes (extensive disease) No major comorbid illnesses Active lifestyle/expect longevity Dedicated to lifestyle changes Great motivation to rehabilitate Thin, athletic in past

Angiographic characteristics Percutaneous intervention better

Coronary bypass better

Focal/limited 1- or 2-vessel CAD Good left ventricular function AHA/ACC type A, Bl lesion Bifurcation: risk to small branch Crossable total occlusion

3-vessel CAD/left main CAD Poor left ventricular function AHA/ACC type B2, C lesion Bifurcation: risk to large branch Uncrossable occlusion/large area of “jeopardized” tissue Stable CAD Goal: survival/symptom relief

Acute MI/cardiogenic shock Procedure goal: symptom relief

Abbreviations: COPD, Chronic obstructive pulmonary disease; CAD, coronary artery disease; AHA/ACC, American Heart Association/American College of Cardiology; MI, myocardial infarction.

The challenge in the near future will be to further define the role for PCI versus CABG, especially in the elderly and patients with extensive CAD and significant comorbidities. Drug-eluting stents, by promising a solution to the problem of restenosis, may well provide the opportunity for multivessel PCI to surpass CABG as the preferred revascularization therapy in general and in the elderly in particular.

GOALS OF REVASCULARIZATION IN THE ELDERLY One drawback of comparing results of angioplasty and PCI in the elderly versus younger patients is that the goals of the procedure may differ by age. More often, elderly patients are poor candidates for surgery, with the palliative goal of reducing symptoms, whereas younger patients are freer to consider the options: either the most effective procedure that will avoid the need for future procedures versus the one that will interfere the least with their active lifestyle. The options in the elderly are often less applicable or consist of picking the “better” of two “unappealing” therapeutic alternatives. In summary, results employing PCI with stenting and careful use of IIb/IIIa inhibitors have advanced interventional methods to a degree where stenting may be the preferred revascularization option in the oldest and/or sickest patients. Hopefully, clinical trialists will continue to address revascularization issues in the elderly, recognizing their unique needs.

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Exercise Training and Cardiac Rehabilitation in Older Cardiac Patients Philip A. Ades Fletcher-Allen Health Care, University of Vermont College of Medicine, Burlington, Vermont, U.S.A.

The goals of cardiac rehabilitation in older coronary populations are to decrease cardiac disability, cardiac-related symptoms, and to extend disability-free survival. Compared with younger patients with coronary heart disease (CHD), older patients have higher rates of disability and mobility limitations, and a diminished exercise capacity (1–3). Coronary artery disease (CAD) in the elderly is also characterized by a greater severity of angiographic disease (4), more severe and more diffuse left ventricular systolic dysfunction (5), and increased levels of peripheral vascular and left ventricular stiffness also termed “diastolic dysfunction,” compared with younger cardiac patients (6). The higher rate of diastolic dysfunction results in the fact that dyspnea is a more common symptom than chest pain in many older patients suffering a myocardial infarction (7,8). Compared with older men, older women with CHD have a higher prevalence of chronic heart failure, a greater prevalence of coronary risk factors, a more complex clinical course, and higher rates of physical disability (1,9). Despite the fact that primary prevention has resulted in a lower prevalence of CAD in the elderly, the rapidly increasing size of the older population is such that the absolute number of older patients with CHD is increasing (10,11). Cardiac rehabilitation exercise training designed to decrease disability and overall coronary risk in older CHD patients should come to play an increasingly important role as the size of the older CHD population continues to grow. CARDIAC DISABILITY The Social Security Administration has no guidelines or definitions for cardiac disability for patients over the age of 65 years, because at this age disability pensions are simply converted to “old-age” pensions (12). In practice, disability in older CHD patients is defined by limitations in physical activity, mobility, and ability to perform activities of daily living with an underlying psychological component. Data from the Framingham Disability Study provides insight into the effects of various CHD manifestations on disability and mobility in older populations (1). The Framingham Disability Study included 2576 participants and yielded a quantitative assessment of levels of physical and 405

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Table 1 Framingham Disability Study by Age and Coronary Disease Status

No CAD or CHF Women Men Coronary heart disease Women Men Angina pectoris Women Men Chronic heart failure Women Men

Percentage with disability (age 55–69 yr)

Percentage with disability (age 70–88 yr)

25 9

49 27

67 49

79 49

67 57

84 56

80 43

88 57

Abbreviations: CHF, chronic heart failure; CAD, coronary artery disease. Source: From Ref. 1.

social disability in older adults, based upon self-reported information. The measures of disability were primarily based upon three questions: “Are you able to walk up and down stairs to the second floor without help?” “Are you able to walk a half mile without help?” and “Are you able to do heavy work around the house, like shoveling snow or washing windows, walls, or floors without help?” The presence of any negative responses determined a component of physical disability. At a given age, women were more likely to report disability than men, and the presence of CHD was a major predictor of activity limitations in both men and women (Table 1). In the 55- to 69-year age group, 49% of men and 67% of women with CHD were disabled as compared with 9% of men and 25% of women without CHD. In coronary patients over the age of 70 years with symptoms of angina pectoris or chronic heart failure, disability was reported by over 80% of women and 55% of men. The presence of CHD in the “older-old” was particularly powerful, with estimated disability rates of up to 76% in men 75 years of age and older. Other studies on this topic are complementary to the Framingham study. In the Medical Outcomes Study, angina was related to the total physical activity score in older patients, although past myocardial infarction was not (13). Chirikos and Nickel studied 976 men and women hospitalized for acute coronary syndromes (myocardial infarction or unstable angina). By multivariate analysis, they found that the presence of cardiac disease, in particular angina pectoris, was predictive of disability at 6, 18, and 24 months of follow-up (14). In a subsequent analysis, they found that angina was more disabling in older women than older men, supporting the findings of the Framingham study (2). Data from our laboratory provides further insight into the determinants of physical functional capacity in older coronary patients (15). A group of 51 men and women over the age of 65 years with established chronic CHD underwent comprehensive evaluations with exercise echocardiography, measurement of peak aerobic capacity, strength, and body composition along with detailed clinical histories, and self-reported measures of physical function and mental depression. Univariate predictors of physical function score included peak aerobic capacity, depression score, handgrip strength, gender, and comorbidity score (16). By multivariate analysis, the only independent predictors of physical function score were peak aerobic capacity and depression score. Left ventricular

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systolic function, which varies inversely with infarct size, was not related to the physical function score (15). In summary, the presence of clinical CHD is a powerful predictor of disability and mobility limitations in the elderly. Disability rates are highest in women, the older-old, and in the presence of angina pectoris, chronic heart failure, and mental depression.

AEROBIC TRAINING The goals of cardiac rehabilitation exercise training in older coronary populations are, above all, to decrease cardiac disability and to extend disability-free survival. These goals are accomplished by programs that will increase aerobic capacity, muscle strength, and flexibility and which will provide associated psychosocial and cardiac risk factor benefits. Exercise training programs in the elderly also need to take into account commonly associated comorbidities that can alter the modalities and intensities of the exercise stimulus that is required. These include, but are not limited to, chronic heart failure, arthritis, chronic lung disease, diabetes, osteoporosis, and peripheral and cerebrovascular disease. In middle-aged coronary patients and in patients with chronic heart failure, reduced cardiovascular fitness [peak oxygen uptake (VO2)] is a primary clinical predictor of impaired physical function and of clinical survival (17,18). Furthermore, favorable training-induced changes in peak aerobic capacity are associated with a lower mortality for patients with the greatest training effect (19). Meta-analyses of randomized trials of cardiac rehabilitation, including over 4000 patients, document a 25% decreased mortality over an average follow-up of three years after cardiac rehabilitation (20,21). These studies are limited, however, by the inclusion of few patients over the age of 65, and the fact that over 80% of the subjects were male. Most of these studies antedated current thrombolytic and interventional approaches to acute myocardial infarction as well as the many interventions available for secondary prevention, such as lipid lowering, antiplatelet therapy, b-adrenergic blockade, and angiotensin-converting–enzyme inhibitors. The Cochrane Database systematic review of cardiac rehabilitation in 2001 extends these findings to contemporary populations, although these remain primarily middle-aged patients (22). In older coronary patients, there are no definitive randomized clinical trial data assessing whether exercise conditioning prolongs life. Therefore, the goals of rehabilitation in the elderly need to focus on improving physical functioning and extending disability-free survival. It should be noted, however, that a large observational study, the British Regional Heart Study of almost 6000 men with established CHD, found that regular light-to-moderate physical activity was associated with a lower five-year all-cause mortality (23). Secondarily, exercise rehabilitation plays an important role in coordination of coronary risk factor therapy, including management of hypertension, lipid abnormalities, insulin resistance, and obesity (24). The cardiac rehabilitation literature supports the safety and efficacy of exercise training regimens in older coronary patients (3,25–28). Compared with younger coronary patients, older patients are significantly less fit at entry into a rehabilitation program one to three months after suffering a major coronary event, such as myocardial infarction or coronary bypass surgery (3,29) (Fig. 1). In a cross-sectional analysis of cardiac patients, peak aerobic capacity decreased by 40% in men and 33% in women from age 40 to age 80 (29). Also notable is that older patients after coronary artery bypass grafting surgery are significantly less fit compared with patients after myocardial infarction or a percutaneous coronary intervention (29). However, after three months of aerobic conditioning, older

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Figure 1 Peak aerobic capacity (peak VO2) by age and gender entering cardiac rehabilitation. Upper graph (hatched lines) are women. Lower graph (solid lines) are men. Abbreviation: VO2, oxygen uptake. Source: From Ref. 29.

Figure 2 Peak aerobic capacity (Peak VO2) before and after conditioning in older and younger patient groups. *p < 0.001 compared with preconditioning. Abbreviation: VO2, oxygen uptake. Source: From Ref. 3.

coronary patients derive a similar relative training benefit as younger patients, with peak VO2 increasing 16% to 20%, effectively distancing themselves from mobility limitations and disability (Fig. 2). Training programs have been extended to a year and longer with long-term maintenance of exercise-related benefits (27,30). The effects of aerobic exercise training programs on submaximal exercise response in older coronary patients are more relevant to the performance of daily activities than the maximal exercise response. In a study of 45 older coronary patients, mean age 69
6 years, subjected to a three-month aerobic conditioning program, submaximal indices of exercise

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performance were closely studied (31). Training effects were assessed during an exhaustive submaximal exercise protocol, with patients exercising at a steady intensity of 80% of a previously measured peak aerobic capacity. Outcome measures included endurance time, serum lactate, perceived exertion, heart rate, blood pressure, and expired ventilatory measures. Exhaustive endurance time increased by more than 40% after conditioning, with associated decreases in serum lactate, perceived exertion, minute ventilation, heart rate, and systolic blood pressure during relatively steady state exercise. Respiratory exchange ratio during steady state exercise, an indicator of substrate utilization, decreased, indicating a shift toward greater use of free fatty acids as a more efficient metabolic fuel. Activities that were exhaustive before training became sustainable for extended periods of time at a lower perceived exertion. The mechanisms of physiological adaptations to aerobic exercise conditioning in the elderly may differ somewhat from those seen in younger (i.e., middle-aged) coronary patients. In younger patients, physiological responses to training include both peripheral adaptations (skeletal muscle and vascular), which result in a widened arteriovenous oxygen difference at maximal exercise (32,33), and cardiac adaptations, which include increases in cardiac dimensions, stroke work, cardiac output, and afterload-corrected indices of left ventricular function (34–37). In older coronary patients, coronary and peripheral vascular diseases are superimposed on “age-related” increases in left ventricular and arterial wall thickness and stiffness (6,8,39), which may reduce their adaptability to remodeling. We found that, after three months of intensive aerobic conditioning in 60 older coronary patients (mean age 68
5 years, range 62–82 years), conditioning-induced adaptations were localized almost exclusively to the periphery (40). Peak exercise cardiac output, hyperemic calf blood flow, and vascular conductance were unaffected by the conditioning program. In contrast, at 3 and 12 months, arteriovenous oxygen difference at peak exercise was increased in intervention subjects but not in age-matched controls, which explains the 16% increase in peak aerobic capacity. Histological analysis of skeletal muscle documented a 34% increase in capillary density and a 23% increase in oxidative enzyme capacity after three months. After 12 months, an increase in individual fiber area was seen compared with baseline measures. Thus, even after 12 months of aerobic exercise, in contrast with middle-aged coronary patients, we saw no discernible improvements in cardiac output or calf blood flow. It is acknowledged, however, that the absolute amount of exercise performed by older coronary patients is less than that performed by younger patients, and this may potentially confound comparisons of physiological response to training by age group. Practical issues related to the implementation of exercise training programs in older coronary patients include the frequent need for training regimens to be adjusted to accommodate the presence of comorbidities such as arthritis, diabetes, and peripheral vascular disease (Table 2). The least fit individuals are often unable to sustain exercise for

Table 2 Implementing Exercise in Older Coronary Patients . Optimally performed in the cardiac rehabilitation setting . Intensity of exercise generally based on an exercise tolerance test . In severely disabled patients, forego exercise test and begin with low level interval training on treadmill and/or cycle . Resistance training based on single-repetition maximal testing . Advance intensity actively . Long-term goals and follow-up

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extended periods and do well with repeated intermittent brief bouts of exercise (often termed “interval training”) that are gradually extended. Some authors recommend longerterm exercise programs for the elderly, partly related to their low baseline functional capacity (30). It should however, be noted, that even patients who use canes and walkers can perform an exercise test and can train on a treadmill with surround bars or on a cycle ergometer. Despite the documented value of exercise regimens in older patients and the low baseline measures of functional capacity, older coronary patients are far less likely than younger patients to participate in cardiac rehabilitation (41). Our data documented a 21% participation rate in cardiac rehabilitation for patients over the age of 62 years who recently suffered a coronary event and who lived within 1 hour driving time of the rehabilitation center, compared with a 4% participation rate in younger patients (41). By far, the most powerful predictor of cardiac rehabilitation participation in the clinical setting was the strength of the primary physician’s recommendation for participation as described by the patient. The physician’s recommendation was scored from 1 to 5, ranging from no encouragement to participate (a score of 1) to a strong encouragement to participate (a score of 5). When the recommendation was weak (a score of 1–3), a 2% participation rate was noted, compared with a rate of 66% when it was strong (a score of 4–5). Older women had a lower participation rate than men (15% vs. 25%; p ¼ 0.06); this difference was primarily related to lower physician recommendation scores for women than men (42). Other factors weighing against participation for women include more comorbid conditions, greater difficulty with transportation, lower likelihood of being married, and higher likelihood of having a dependent spouse at home.

RESISTANCE TRAINING Resistance training has been advocated as a particularly useful intervention in older coronary patients for several reasons (43–45). First and foremost, even “normal” aging is associated with a significant loss of muscle mass and strength, related both to diminished activity profiles and to decreased rates of muscle protein synthesis (43,46–48). Furthermore, in older populations ranging from healthy community living elders to institutionalized octogenarians, resistance training has been demonstrated to improve walking endurance, muscle mass, and strength (49,50). In coronary patients, aging-related musculoskeletal abnormalities are superimposed upon activity restrictions related to chronic disease (51), and diminished muscle mass and strength, termed “sarcopenia,” is even more severe. In a study that focused upon resistance training in older CAD patients who had recently suffered a myocardial infarction, relative increases in strength were found to be similar to increases seen in younger CAD patients (44). In older women with chronic CHD, where the negative effects of age, gender, and chronic disease all conspire to result in a severe loss of strength and function (15), the effects of strength training have recently been studied (52). Brochu et al. assessed the effects of six months of resistance training on strength, endurance, and on a physical performance test designed to assess physical function during practical household activities in 30 older women, mean age 71
5 years (53). Compared with patients randomized to a control group, strength-trained women increased strength, endurance, and capacity to perform a wide range of household activities such as carrying groceries, doing household activities, and climbing stairs. The increase in strength after resistance training correlated with improvements in the overall physical function score (Fig. 3).

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Figure 3 Association between percent changes in total CS-PFP and percent changes in maximal strength on the bench press before and after strength training in older women with coronary heart disease. Abbreviation: CS-PFP, continuous scale physical functional performance test score. Source: From Ref. 52.

From a practical point of view, the onset of upper body resistance training should be delayed until three months after coronary bypass surgery to allow for full sternal healing, while it can commence as soon as one month of postmyocardial infarction after performance of a satisfactory baseline exercise tolerance test. The resistance training program should include training of the leg extensor muscles to assist with walking, stair climbing and fall prevention, and upper body training to aid in the lifting and pushing required for the performance of daily household activities. Training is based upon the performance of a single-repetition maximal (1-RM) lift supplemented by a Borg scale for perceived exertion (54). Patients begin their resistance training with 8 to 10 repetitions of each exercise at 40% to 50% of their 1-RM for a given exercise and gradually increase exercise intensity, as tolerated, to 50% to 80% of updated 1-RMs. SCREENING AND IMPLEMENTATION Optimally, older coronary patients begin exercise training only after a careful screening process, which should include an electrocardiographically monitored exercise tolerance test, strength measures, and a clinical review, including an analysis of disease severity and questionnaire or interview-derived data regarding physical and psychosocial function. Diagnostic categories appropriate for consideration of cardiac rehabilitation exercise training in older cardiac patients include myocardial infarction, stable angina pectoris, coronary bypass surgery, percutaneous coronary revascularization (angioplasty, or stenting), heart valve replacement, and chronic heart failure. Exercise modalities should include options for aerobic, resistance, and flexibility exercise. Aerobic choices include treadmills, a walking course, cycles, airdynes, and rowers. Aerobic exercise is often guided by an exercise heart rate range and/or scales of perceived exertion such as the Borg scale. A gradual increment of exercise heart rate from

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60% to 65% of maximal attained heart rate to higher levels of up to 85% is balanced against the greater risk of injury at higher levels and past demonstration of measurable benefits even with low levels of exercise (55). It has been observed that older coronary patients are less likely to exercise to a physiological maximum at their baseline exercise test than younger patients; therefore, strict adherence to an exercise heart rate range is often inappropriate (3). Duration of the exercise stimulus can begin with very brief, intermittent bouts of exercise, gradually increasing to 20 to 25 minutes or longer. Special considerations in the elderly include that training regimens often need to be adjusted to accommodate the presence of comorbidities. For example, patients with hip or knee arthritis may do better with cycling or rowing exercises to avoid the weight bearing of treadmill walking. However, walking is generally a preferred modality because of its direct relevance to daily activities. Finally, it should be noted that, for many elders, flexibility, or lack thereof, can be an exercise-limiting factor. Flexibility exercises can be as simple as 5 to 10 minutes of stretching per day to more complex protocols of yoga and tai chi. Gender Issues Healthy older women have lower levels of habitual physical activity and physical functioning than older men, explained, in part, by lower strength and muscle mass (56–58). Older women with CAD further curtail their activities because of apprehension regarding the safety of specific physical activities, which compounds their deconditioning. Following a coronary event, women have lower fitness levels than men (29), yet are less likely to be referred to an exercise-based rehabilitation program by their physicians (41). This distinction may relate, in part, to the older age of women after infarction, compared with men, or to higher rates of angina pectoris, but is most likely related to the physician misunderstanding regarding the benefits of rehabilitation in the most severely debilitated patients. Women make similar improvements in aerobic fitness and in muscular strength compared with men in rehabilitation programs (43,44). The current model of cardiac rehabilitation was developed primarily in middle-aged male coronary patients in the 1960s and 1970s. The differing clinical profile of women in cardiac rehabilitation may require a different model relevant to their older age, increased prevalence of comorbid conditions, more prominent cardiac risk factor profiles, higher rates of depression, higher risk of recurrent coronary events, and differing personal preferences (59–62). Supervised Vs. Home Exercise Roughly, only 15% of eligible patients in the United States receive cardiac rehabilitation services, with the lowest participation rates noted in older patients (24,41). In many cases, cardiac rehabilitation programs are not geographically available (63), whereas in other cases, patients are unable to travel, or the primary physician does not recommended formal rehabilitation. While cardiac rehabilitation services have classically been delivered on-site at an established exercise training facility, a need to expand preventive cardiology services to include the majority of eligible patients in a cost-effective manner necessitates a redefinition of this classical model. The development of alternate approaches to the delivery of cardiac rehabilitation services is an ongoing process, with a goal of expanding the base of patients who receive services at the lowest possible healthcare costs. Older patients tend to require a more “hands-on” approach early in the rehabilitative process, but often can transition to

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a home program with appropriate follow-up. Case management, that is, evaluation and management of the exercise program and risk factors for the individual patient by a nurse “case manager” allows for the individualization of preventive care in health-care delivery systems that focus on efficiency and outcomes. Exercise programs can be individualized, with moderate- and high-risk patients referred to a rehabilitation program for closer supervision and monitoring. CARDIAC REHABILITATION ON CORONARY RISK FACTORS Exercise plays an important adjunctive role in the management of blood lipid levels, obesity, blood pressure, and psychological factors such as social isolation and mental depression. In older coronary populations, exercise rehabilitation has well-defined metabolic benefits that include improved blood lipid values, decreased body fat, improved glucose tolerance, and lower blood pressure (28,64,65). In addition, cardiac rehabilitation in the elderly has been shown to have important effects on mental health, which include decreased measures of depression, anxiety, and hostility (Table 3) (66–69). These measures, in summary, constitute important outcome measures for older CHD patients engaging in therapeutic exercise. Cardiac rehabilitation programs have been termed “secondary prevention centers” and thus should function as a location to systematically measure and treat coronary risk factors with both lifestyle approaches (exercise and nutrition) and pharmacological therapy. For example, a systematic approach to measuring lipid profiles in all patients entering cardiac rehabilitation, with an active stance towards pharmacological therapy, resulted in a tripling of the number of patients that attain nationally recognized therapeutic lipid goals (70). Similarly, blood-pressure monitoring and treatment, and obesity assessment and treatment should be coordinated in the cardiac rehabilitation setting (71). The magnitude of exercise-related effects on blood lipid measures depends, in part, on whether or not there is associated weight loss. In a study of cardiac rehabilitation without weight loss, lipid effects were relatively modest with high density lipoprotein (HDL)-cholesterol increasing by 8%, but no significant effects on low density lipoprotein (LDL)-cholesterol, triglyceride levels, or glucose levels (64). On the other hand, when exercise was associated with 10 lbs of exercise-induced weight loss, favorable effects were noted on serum triglycerides (–24%), HDL-cholesterol (þ7%), on the atherogenic ratio [total cholesterol/HDL-cholesterol (–14%)], and fasting serum insulin levels (–22%) (72). Exercise rehabilitation has also been shown to be associated with a decrease in the high-sensitive C-reactive protein, a predictor of prognosis after myocardial infarction Table 3 Noncardiac Benefits of Exercise Rehabilitation in Older Coronary Patients Effect

Ref.

Increased HDL cholesterol (þ810%) Decreased triglycerides (1025%) Decreased body fat (12%) Improved glucose tolerance Lowered blood pressure (57 mmHg systolic) Diminished depression, anxiety, and hostility

28,64

Abbreviation: HDL, high-density lipoprotein.

28,64 65 66 28,67–69

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(73). The benefits in older coronary patients of lipid-lowering, smoking-cessation, angiotensin-converting–enzyme inhibition, antiplatelet agents, and b-adrenergic blockade have all been demonstrated in appropriately selected populations (74,75). FUTURE DIRECTIONS As the older cardiac population continues to grow in size and complexity, the role of cardiac rehabilitation in the elderly should proportionately expand. The effects of aerobic and resistance-training protocols on measures of physical functioning need to be better studied in older coronary populations, with the inclusion of patients disabled by angina or chronic heart failure. Whether training regimens can improve physical functioning in the most severely disabled patients is of particular importance, although preventing disability in the less severely affected “younger-old” is also a priority. Effects of exercise regimens on other important outcomes, including lipid levels, blood pressure measures, insulin levels, body composition, and body fat distribution need to be further studied to better define expected benefits of rehabilitation. Finally, whether training regimens can affect the economics of health care is crucial, especially if costly hospitalizations and/or homecare services can be minimized. In summary, the older coronary population is a highly disabled group, yet quite heterogeneous as to physical functioning and disease severity. Cardiac rehabilitation training programs have been demonstrated to be safe and to improve aerobic fitness capacity, muscular strength, and cardiac risk factors. Exercise training may, in fact, reverse and prevent cardiac disability. Thus, cardiac rehabilitation can pay great medical, social, and economic dividends in the older coronary population. REFERENCES 1. Pinsky JL, Jette AM, Branch LG, et al. The Framingham Disability Study: relationship of various coronary heart disease manifestations to disability in older persons living in the community. Am J Publ Health 1990; 80:1363–1368. 2. Nickel JT, Chirikos TN. Functional disability of elderly patients with long-term coronary heart disease: a sex-stratified analysis. J Geront 1990; 45:560–568. 3. Ades PA, Grunvald MH. Cardiopulmonary exercise testing before and after conditioning in older coronary patients. Am Heart J 1990; 120:585–589. 4. Sugiura M, Hiraoka K, Ohkawa S. Severity of coronary sclerosis in the aged: a pathological study of 968 consecutive autopsy cases. Jpn Heart J 1976; 17:471–478. 5. Hochman J, Boland J, Sleeper L. Current spectrum of cardiogenic shock and effect of early revascularization on mortality: results of an international registry. Circulation 1995; 91:873–881. 6. Rockman HA, Lew W. Left ventricular remodeling and diastolic dysfunction in chronic ischemic heart disease. In: Gaasch WH, LeWinter MM, eds. Left Ventricular Diastolic Dysfunction and Heart Failure. Philadelphia, PA: Lea and Febiger, 1994. 7. Bayer A, Chadha J, Farad R, et al. Changing presentation of myocardial infarction with increasing old age. J Am Geriatr Soc 1986; 34:263–266. 8. Solomon C, Lee T, Cook E, et al. Comparison of clinical presentation of acute myocardial infarction in patients older than 65 years of age to younger patients: the multicenter chest pain study experience. Am J Cardiol 1989; 63:772–776. 9. Malacrida R, Genoni M, Maggioni A, et al. A comparison of the early outcome of acute myocardial infarction in women and men. New Engl J Med 1998; 338:8–14. 10. Weinstein W, Coxson P, Williams L, et al. Forecasting coronary heart disease incidence, mortality and cost: The Coronary Heart Disease Policy Model. Am J Publ Health 1987; 77:1417–1426.

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35. Hagberg JM, Ehsani AA, Holloszy JO. Effects of 12 months of intense exercise training on stroke volume in patients with coronary artery disease. Circulation 1983; 67:1194–1199. 36. Ehsani AA, Biello DR, Schultz J, et al. Improvement of left ventricular contractile function by exercise training in patients with coronary artery disease. Circulation 1986; 74:350–358. 37. Hagberg JM. Physiologic adaptations to prolonged high-intensity exercise training in patients with coronary artery disease. Med Sci Sports 1991; 23:661–667. 38. Lakatta E, Mitchell J, Pomerance A, et al. Human aging: changes in cardiac structure and function. J Am Coll Cardiol 1987; 10:42A–47A. 39. Vaitkevicius P, Fleg J, Engel J, et al. Effects of age and aerobic capacity on arterial stiffness in healthy adults. Circulation 1993; 88:1456–1462. 40. Ades P, Waldmann ML, Meyer WL, et al. Skeletal muscle and cardiovascular adaptations to exercise conditioning in older coronary patients. Circulation 1996; 94:323–330. 41. Ades PA, Waldmann ML, McCann W, et al. Predictors of cardiac rehabilitation participation in older coronary patients. Arch Intern Med 1992; 152:1033–1035. 42. Ades PA, Waldmann ML, Polk D, et al. Referral patterns and exercise response in the rehabilitation of female coronary patients aged  62 years. Am J Cardiol 1992; 69:1422–1425. 43. Brechue W, Pollack M. Exercise training for coronary artery disease in the elderly. Clin Geriatr Med 1996; 1:207–229. 44. Fragnoli-Munn K, Savage P, Ades P. Combined resistive-aerobic training in older coronary patients early after myocardial infarction. J Cardiopulm Rehabil 1998; 18:416–420. 45. Squires RW, Muri AJ, Amderson LJ, et al. Weight training during phase II (early outpatient) cardiac rehabilitation: heart rate and blood pressure responses. J Cardiopulm Rehabil 1991; 11:360–364. 46. Frontera W, Meredith CN, O’Reilly KP, et al. Strength conditioning in older men: skeletal muscle hypertrophy and improved function. J Appl Physiol 1988; 64:1038–1044. 47. Frontera WR, Meridith CN, O’Reilly KP, et al. Strength training and determinants of VO2 max. J Appl Physiol 1990; 68:329–333. 48. Balagopal P, Rooyackers O, Adey D, et al. Effects of aging on In-Vivo synthesis of skeletal muscle myosin heavy chain and sarcoplasmic protein in humans. Am J Physiol 1997; 273: E790–E800. 49. Ades PA, Ballor DL, Ashikaga T, et al. Weight training improves walking endurance in the healthy elderly. Ann Intern Med 1996; 124:568–572. 50. Fiatorone MA, Marks EC, Ryan ND, et al. High intensity strength training in nonagenarians: effects of skeletal muscle. JAMA 1990; 263:3029–3034. 51. Neill WA, Branch LG, DeJong G. Cardiac disability: the impact of coronary disease on patients’ daily activities. Arch Intern Med 1981; 145:1642–1647. 52. Brochu M, Savage P, Lee N, et al. Effects of resistance training on physical function in older disabled women with coronary heart disease. J Appl Physiol 2002; 92:672–678. 53. Cress ME, Buchner DM, Questad KA, et al. Continuous-scale physical functional performance in a broad range of older adults: a validation study. Arch Phys Med Rehabil 1996; 7:1243–1250. 54. Borg GA. Perceived exertion: a note on history and methods. Med Sci Sports 1973; 5:90–93. 55. Lee JY, Jensen BE, Oberman A, et al. Adherence in the training levels comparison trial. Med Sci Sports Exerc 1996; 28(l):47–52. 56. Reaven PD, McPhillips JB, Barrett-Connor EL, et al. Leisure time exercise and lipid and lipoprotein levels in an older population. J Am Geriatr Soc 1990; 38:847–854. 57. Cress M. Quantifying physical functional performance in older adults. Muscle Nerve 1997; 5:S17–S20. 58. Wells CL, Plowman SA. Sexual differences in athletic performance: biological or behavioral? Phys Sportsmed 1983; 11:52–63. 59. Bueno H. Influence of sex on the short-term outcome of elderly patients with a first acute myocardial infarction. Circulation 1995; 92:1133–1140. 60. Cannistra LB, Balady GJ, O’Malley CJ, et al. Comparison of the clinical profile and outcome of women and men in cardiac rehabilitation. Am J Cardiol 1992; 69:1274–1279.

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61. Rich MW, Bosner MS, Chung MK, et al. Is age an independent predictor of early and late mortality in patients with acute myocardial infarction? Am J Med 1992; 92:7–13. 62. Moore SM, Kramer FM. Women’s and men’s preferences for cardiac rehabilitation program features. J Cardiopulm Rehabil 1996; 16:163–168. 63. Curnier D, Savage PD, Ades PA. Geographic distribution of cardiac rehabilitation programs in the U.S. J Cardiopulm Rehabil 2005; 25:80–84. 64. Brochu M, Poehlman ET, Savage P, et al. Modest effects of exercise training alone on coronary risk factors and body composition in coronary patients. J Cardiopulm Rehabil 2000; 20:180–188. 65. Dylewicz P, Bienkowska S, Szczesniak S, et al. Beneficial effect of short-term endurance training on glucose metabolism during rehabilitation after coronary bypass surgery. Chest 2000; 117:47–51. 66. Kokkinos PF, Papademetriou V. Exercise and hypertension. Coron Artery Dis 2000; 11:99–102. 67. Ades PA, Maloney AE, Savage P, et al. Determinants of physical function in coronary patients: response to cardiac rehabilitation. Arch Intern Med 1999; 159:2357–2360. 68. Milani RV, Lavie CJ. Prevalence and effects of cardiac rehabilitation on depression in the elderly with coronary heart disease. Am J Cardiol 1998; 81:1233–1236. 69. Lavie CV, Milani RV. Impact of aging on hostility in coronary patients and effects of cardiac rehabilitation and exercise training in elderly persons. Am J Geriatr Cardiol 2004; 13:125–130. 70. Ades PA, Savage PD, Poehlman ET, et al. Lipid lowering in the cardiac rehabilitation setting. J Cardiopulm Rehabil 1999; 19:255–260. 71. Savage PD, Ades PA. The obesity epidemic in the United States: role of cardiac rehabilitation Cor Art Dis 2006; 17:227–231. 72. Savage P, Brochu M, Poehlman E, et al. Reduction in obesity and coronary risk factors after high caloric exercise training in overweight coronary patients. Am Heart J 2003; 146:317–323. 73. Milani RV, Lavie CJ, Mehra MR. Reduction in C-reactive protein through cardiac rehabilitation and exercise training. J Am Coll Cardiol 2004; 43:1056–1061. 74. Williams MA, Fleg JL, Ades PA, et al. Secondary prevention of coronary heart disease in the elderly (with emphasis on patients  years of age). Circulation 2002; 105:1735–1743. 75. Smith SC Jr. Secondary prevention in the elderly. Coron Artery Dis 1998; 9:715–718.

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Aortic Valve Disease in the Elderly Wilbert S. Aronow Divisions of Cardiology, Geriatrics, and Pulmonary/Critical Care, Department of Medicine, New York Medical College, Valhalla, New York, U.S.A.

Melvin B. Weiss Department of Medicine, Division of Cardiology, New York Medical College/Westchester Medical Center, Valhalla, New York, U.S.A.

AORTIC STENOSIS Etiology and Prevalence Valvular aortic stenosis (AS) in elderly patients is usually due to stiffening, scarring, and calcification of the aortic valve leaflets. The commissures are not fused as in rheumatic AS. Calcific deposits in the aortic valve are common in elderly patients and may lead to valvular AS (1–7). Aortic cuspal calcium was present in 295 of 752 men (36%), mean age 80 years, and in 672 of 1663 women (40%), mean age 82 years (6). Of 2358 patients, mean age 81 years, 378 (16%) had valvular AS, 981 (42%) had valvular aortic sclerosis (thickening of or calcific deposits on the aortic valve cusps with a peak flow velocity across the aortic valve
1.5 m/sec), and 999 (42%) had no valvular AS or aortic sclerosis (7). Calcific deposits in the aortic valve were present in 22 of 40 necropsy patients (55%) aged 90 to 103 years (2). Calcium of the aortic valve and mitral annulus may coexist (1–3,8,9). In the Helsinki Aging study, calcification of the aortic valve was diagnosed by Doppler echocardiography in 28% of 76 patients aged 55 to 71 years, in 48% of 197 patients aged 75 to 76 years, in 55% of 155 patients aged 80 to 81 years, and in 75% of 124 patients aged 85 to 86 years (5). Aortic valve calcification, aortic sclerosis, and mitral annular calcium (MAC) are degenerative processes (1,2,10–12) accounting for their high prevalence in an elderly population. Otto et al. (11) demonstrated that the early lesion of degenerative AS is an active inflammatory process with some similarities to atherosclerosis, including lipid deposition, macrophage and T-cell infiltration, and basement membrane disruption. In a prospective study of 571 unselected patients, mean age 82 years, 292 patients (51%) had calcified or thickened aortic cusps or root (13). A total serum cholesterol greater than or equal

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to 200 mg/dL, a history of hypertension, diabetes mellitus, and a serum high-density lipoprotein cholesterol less than 35 mg/dL were more prevalent in elderly patients with calcified or thickened aortic cusps or root than in elderly patients with normal aortic cusps and root (13). In the Helsinki Aging Study, age, hypertension, and a low body mass index were independent predictors of aortic valve calcification (14). In 5201 patients older than 65 years of age in the Cardiovascular Health Study, independent clinical factors associated with degenerative aortic valve disease included age, male gender, smoking, history of hypertension, height, and high lipoprotein (a) and low-density lipoprotein cholesterol levels (12). In 1275 elderly patients, mean age 81 years, AS was present in 52 of 202 patients (26%) with 40% to 100% extracranial carotid arterial disease (ECAD) and in 162 of 1073 patients (15%) with 0% to 39% ECAD (15). In 2987 elderly patients, mean age 81 years, symptomatic peripheral arterial disease was present in 193 of 462 patients (42%) with AS and in 639 of 2525 patients (25%) without AS (16). In 290 patients, mean age 79 years, with valvular AS who had follow-up Doppler echocardiograms, elderly patients with MAC had a greater reduction in aortic valve area/ year than those without MAC (17). Cigarette smoking and hypercholesterolemia were significant independent risk factors for the progression of valvular AS in 102 patients, mean age 76 years, who had follow-up Doppler echocardiograms (18). Palta et al. (19) also found that cigarette smoking and hypercholesterolemia accelerate the progression of AS. These and other data suggest that aortic valve calcium, MAC, and coronary atherosclerosis in elderly patients have similar predisposing factors (11–21). A retrospective analysis of 180 elderly patients with mild AS who had follow-up Doppler echocardiograms at or after two years showed that significant independent predictors of the progression of AS were male gender, cigarette smoking, hypertension, diabetes mellitus, a serum low-density lipoprotein cholesterol greater than or equal to 125 mg/dL at follow-up, a serum high-density lipoprotein cholesterol less than 35 mg/dL at follow-up, and use of statins (inverse association) (22). Novaro et al. (23) reported in a retrospective analysis of 174 patients, mean age 68 years, with mild to moderate AS that statin therapy reduced the progression of AS. In a retrospective study of 156 patients, mean age 77 years, with AS, at 3.7-year follow-up, statin therapy reduced the progression of AS by 54% (24). There is need for data from a long-term, large, prospective, randomized controlled trial of intensive statin therapy in patients with AS, especially in patients with mild AS. The frequency of AS increases with age. Valvular AS diagnosed by Doppler echocardiography was present in 141 of 924 men (15%), mean age 80 years, and in 322 of 1881 women (17%), mean age 81 years (25). Severe valvular AS (peak gradient across aortic valve of 50 mmHg or aortic valve area <0.75 cm2) was diagnosed in 62 of 2805 elderly patients (2%) (25). Moderate valvular AS (peak gradient across aortic valve of 26–49 mmHg or aortic valve area of 0.75–1.49 cm2) was present in 149 of 2805 elderly patients (5%) (25). Mild valvular AS (peak gradient across aortic valve of 10–25 mmHg or aortic valve area 1.50 cm2) occurred in 25 of 2805 elderly patients (9%) (25). In 924 elderly men, mean age 80 years, AS was present in 36 of 236 African-Americans (15%), in 19 of 135 Hispanics (14%), and in 86 of 553 whites (16%) (25). In 1881 elderly women, mean age 81 years, AS was present in 84 of 494 African-Americans (17%), in 33 of 188 Hispanics (18%), and in 205 of 1199 white women (17%) (25). In 501 unselected patients aged 75 to 86 years in the Helsinki Aging Study, critical AS was present in 3% and moderate to severe AS in 5% of the 501 elderly patients (5).

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Pathophysiology In valvular AS, there is resistance to ejection of blood from the left ventricle (LV) into the aorta, with a pressure gradient across the aortic valve during systole and an increase in LV systolic pressure. The pressure overload on the LV leads to concentric LV hypertrophy, with an increase in LV wall thickness and mass, normalizing systolic wall stress, and maintenance of normal LV ejection fraction and cardiac output (26,27). A compensated hyperdynamic response is common in elderly women (28). Elderly patients with a comparable degree of AS have more impairment of LV diastolic function than do younger patients (29). Coronary vasodilator reserve is more severely impaired in the subendocardium in patients with LV hypertrophy caused by severe AS (30). The compensatory concentric LV hypertrophy leads to abnormal LV compliance, LV diastolic dysfunction with reduced LV diastolic filling, and increased LV end-diastolic pressure, further increased by left atrial systole. It also develops left atrial enlargement. Atrial systole plays an important role in diastolic filling of the LV in patients with AS (31). Loss of effective atrial contraction may cause immediate clinical deterioration in patients with severe AS. Sustained LV hypertrophy eventually leads to LV chamber dilatation with decreased LV ejection fraction and, ultimately, congestive heart failure (CHF). The stroke volume and cardiac output decrease, the mean left atrial and pulmonary capillary pressures increase, and pulmonary hypertension occurs. Elderly patients with both obstructive and nonobstructive coronary artery disease (CAD) have an increased incidence of LV enlargement and LV systolic dysfunction (32). In a percentage of elderly patients with AS, the LV ejection fraction will remain normal and LV diastolic dysfunction will be the main problem. In 48 elderly patients with CHF associated with unoperated severe valvular AS, the LV ejection fraction was normal in 30 patients (63%) (33). The prognosis of patients with AS and LV diastolic dysfunction is usually better than that of patients with AS and LV systolic dysfunction, but is worse than that of patients without LV diastolic dysfunction (33,34). Symptoms Angina pectoris, syncope or near syncope, and CHF are the three classic manifestations of severe AS. Angina pectoris is the most common symptom associated with AS in elderly patients. Coexistent CAD is frequently present in these patients. However, angina pectoris may occur in the absence of CAD as a result of an increase in myocardial oxygen demand with a reduction in myocardial oxygen supply at the subendocardial level. Myocardial ischemia in patients with severe AS and normal coronary arteries is due to inadequate LV hypertrophy with increased LV systolic and diastolic wall stresses causing decreased coronary flow reserve (35). Syncope in patients with AS may be caused by reduced cerebral perfusion following exertion when arterial pressure drops because of systemic vasodilatation in the presence of a fixed cardiac output. LV failure with a decrease in cardiac output may also cause syncope. In addition, syncope at rest may be caused by a marked reduction in cardiac output secondary to transient ventricular fibrillation or transient atrial fibrillation (AF) or transient atrioventricular block related to extension of the valve calcification into the conduction system. Coexistent cerebrovascular disease with transient cerebral ischemia may contribute to syncope in elderly patients with AS. Exertional dyspnea, paroxysmal nocturnal dyspnea, orthopnea, and pulmonary edema may be caused by pulmonary venous hypertension associated with AS. Coexistent

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CAD and hypertension may contribute to CHF in elderly patients with AS. AF may also precipitate CHF in these patients. CHF, syncope, or angina pectoris was present in 36 of 40 elderly patients (90%) with severe AS, in 66 of 96 elderly patients (69%) with moderate valvular AS, and in 45 of 165 elderly patients (27%) with mild valvular AS (36). Sudden death occurs mainly in symptomatic valvular AS patients (33,36–39). It may also occur in 3–5% of asymptomatic patients with AS (37,39). Marked fatigue and peripheral cyanosis in patients with AS may be caused by a low cardiac output. Cerebral emboli causing stroke or transient cerebral ischemic attack, bacterial endocarditis, and gastrointestinal bleeding may also occur in elderly patients with AS. Signs A systolic ejection murmur heard in the second right intercostal space, down the left sternal border toward or at the apex is classified as an aortic systolic ejection murmur (ASEM) (3,4,40,41). An ASEM is commonly heard in elderly patients (1,3,40), occurring in 265 of 565 unselected elderly patients (47%) (3). Of 220 elderly patients with an ASEM and technically adequate M-mode and two-dimensional echocardiograms of the aortic valve, 207 (94%) had aortic cuspal or root calcification or thickening (3). Of 75 elderly patients with an ASEM, valvular AS was diagnosed by continuous-wave Doppler echocardiography in 42 patients (56%) (41). Table 1 shows that an ASEM was heard in 100% of 19 elderly patients with severe AS, 100% of 49 elderly patients with moderate AS, and 95% of 74 elderly patients with mild AS (4). However, the ASEM may become softer or absent in patients with CHF associated with severe AS because of a low cardiac output. The intensity and maximal location of the ASEM and transmission of the ASEM to the right carotid artery do not differentiate among mild, moderate, and severe AS (3,4,41). The ASEM may be heard only at the apex in some elderly patients with AS. The apical systolic ejection murmur may also be louder and more musical than the basal systolic ejection murmur in some elderly patients with AS. The intensity of the ASEM in valvular AS increases with squatting and by inhalation of amyl nitrite and decreases during the Valsalva maneuver. Prolonged duration and late peaking of the ASEM best differentiate severe AS from mild AS (3,4,41). However, the physical signs do not distinguish between severe and moderate AS (Table 1) (4,41). Table 1 Correlation of Physical Signs of Valvular Aortic Stenosis with the Severity of Aortic Stenosis in Elderly Patients Severity of AS Physical sign ASEM Prolonged duration ASEM Late-peaking ASEM Prolonged carotid upstroke time A2 absent A2 decreased or absent

Mild (n ¼ 74) (%)

Moderate (n ¼ 49) (%)

Severe (n ¼ 19) (%)

95 3 3 3 0 5

100 63 63 33 10 49

100 84 84 53 16 74

Abbreviations: AS, aortic stenosis; ASEM, aortic systolic ejection murmur; A2, aortic component of second heart sound. Source: Adapted from Ref. 4.

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A prolonged carotid upstroke time does not differentiate between severe and moderate AS in elderly patients (4). A prolonged carotid upstroke time was palpable in 3% of elderly patients with mild AS, in 33% of elderly patients with moderate AS, and in 53% of elderly patients with severe AS (Table 1) (4). Stiff noncompliant arteries may mask a prolonged carotid upstroke time in elderly patients with severe AS. The pulse pressure may also be normal or wide rather than narrow in elderly patients with severe AS because of loss of vascular elasticity. An aortic ejection click is rare in elderly patients with severe AS because of loss of vascular elasticity. An aortic ejection click is rare in elderly patients with AS because the valve cusps are immobile (4,41). An absent or decreased A2 occurs more frequently in elderly patients with severe or moderate AS than in patients with mild AS (Table 1) (4,41). However, an absent or decreased A2 does not differentiate between severe and moderate AS (4,41). The presence of AF, reversed splitting of S2, or an audible fourth heart sound at the apex also does not differentiate between severe and moderate AS in elderly patients (41). The presence of a third heart sound in elderly patients with AS usually indicates the presence of LV systolic dysfunction and elevated LV filling pressure (42).

Electrocardiography and Chest Roentgenography Table 2 shows that echocardiography is more sensitive than electrocardiography in detecting LV hypertrophy in elderly person with AS (4). Rounding of the LV border and apex may occur as a result of concentric LV hypertrophy. Poststenotic dilatation of the ascending aorta is commonly seen. Calcification of the aortic valve is best seen by echocardiography or fluoroscopy. Involvement of the conduction system by calcific deposits may occur in elderly patients with AS. In a study of 51 elderly patients with AS who underwent aortic valve replacement, conduction defects occurred in 58% of 31 patients with MAC and in 25% of 20 patients without MAC (9). In another study of 77 elderly patients with AS, first-degree atrioventricular block occurred in 18% of patients, left bundle branch block in 10% of patients, intraventricular conduction defect in 6% of patients, right bundle branch block in 4% of patients, and left axis deviation in 17% of patients (43). Complex ventricular arrhythmias may be detected by 24-hour ambulatory electrocardiograms in patients with AS. Elderly patients with complex ventricular arrhythmias associated with AS have a higher incidence of new coronary events than elderly patients with AS and no complex ventricular arrhythmias (44).

Table 2 Prevalence of Electrocardiographic and Echocardiographic LVH in Elderly Patients with Mild, Moderate, and Severe Valvular AS Severity of Valvular AS

Electrocardiographic LVH Echocardiographic LVH

Mild (n ¼ 74) (%)

Moderate (n ¼ 49) (%)

Severe (n ¼ 19) (%)

11 74

31 96

58 100

Abbreviations: AS, aortic stenosis; LVH, left ventricular hypertrophy. Source: Adapted from Ref. 4.

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Echocardiography and Doppler Echocardiography M-mode and two-dimensional echocardiography and Doppler echocardiography are very useful in the diagnosis of AS. Of 83 patients with CHF or angina pectoris and a systolic precordial murmur in whom severe AS was diagnosed by Doppler echocardiography, AS was not clinically diagnosed in 28 patients (34%) (45). Echocardiography can detect thickening, calcification, and reduced excursion of aortic valve leaflets (3). LV hypertrophy is best diagnosed by echocardiography (4). Chamber dimensions and measurements of LV end-systolic and end-diastolic volumes, LV ejection fraction, and assessment of global and regional LV wall motion give important information on LV systolic function. Doppler echocardiography is used to measure peak and mean transvalvular gradients across the aortic valve and to identify associated valve lesions. Aortic valve area can be calculated by the continuity equation using pulsed Doppler echocardiography to measure LV outflow tract velocity, continuous-wave Doppler echocardiography to measure transvalvular flow velocity, and two-dimensional long-axis view to measure LV outflow tract area (46,47). Aortic valve area can be detected reliably by the continuity equation in elderly patients with AS (47). Figures 1 through 5 illustrate two-dimensional echocardiographic findings (Figs. 1 and 3), continuous-wave Doppler echocardiographic findings (Figs. 2 and 4), and simultaneous LV and femoral arterial pressure tracings (Fig. 5) in elderly patients with severe valvular AS. Shah and Graham (48) reported that the agreement in quantitation of the severity of AS between Doppler echocardiography and cardiac catheterization was greater than 95%.

Figure 1 Two-dimensional echocardiographic image from a parasternal long-axis view of a 93-year-old female with aortic stenosis and moderately depressed left ventricular function showing a fibrotic aortic valve and mitral annular calcification. Abbreviations: PS-LAX, parasternal longaxis view; RV, right ventricular cavity; LV, left ventricular cavity; IVS, interventricular septum; PW, posterior wall; CA ANUL, mitral annulus calcification; LA, left atrium; AO, aorta.

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Figure 2 Continuous-wave Doppler recording of the velocity profile across the aortic valve in the same patient shown in Figure 1. A 52 mmHg gradient across the aortic valve is measured using the Bernoulli equation. Indexed aortic valve area measured by the continuity equation using Doppler data ¼ 0.5 cm2/m2.

Figure 3 Two-dimensional echocardiographic image obtained in the same patient in Figures 1 and 2 from a short-axis parasternal view in which the aortic valve orifice is mapped, yielding an indexed area of 0.4 cm2/m2.

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Figure 4 Continuous-wave Doppler recording of the velocity profile across the aortic valve in an elderly patient with aortic stenosis and normal left ventricular systolic function. The indexed aortic valve area is 0.5 cm2/m2 by both Gorlin’s formula and the Doppler continuity equation. The peak gradient across the aortic valve by Bernoulli’s equation is 81 mmHg, a value higher than that recorded in Figure 2 for the same indexed aortic valve area.

Figure 5 Simultaneous left ventricular and femoral artery pressure recordings obtained in the same patient in Figure 4 confirming a large gradient across the aortic valve with a maximum value of 81 mmHg (instantaneous pressure). Abbreviations: Fem. Art., femoral artery pressure tracing; LV, left ventricular pressure tracing.

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Patients with a peak jet velocity greater than or equal to 4.5 m/sec had critical AS, and those with a peak jet velocity less than 3 m/sec had noncritical AS. Slater et al. (49) demonstrated a concordance between Doppler echocardiography and cardiac catheterization in the decision to operate or not to operate in 61 of 73 patients (84%) with valvular AS. In 75 patients, mean age 76 years, with valvular AS, the Bland–Altman plot showed that four of the 75 patients (5%) had disagreement between cardiac catheterization and Doppler echocardiography that was outside the 95% confidence limits (50). Cardiac catheterization was performed in 105 patients in which Doppler echocardiography demonstrated an aortic valve area less than or equal to 0.75 cm2 or a peak jet velocity greater than or equal to 4.5 m/sec, consistent with critical AS (51). Doppler echocardiography was 97% accurate in this subgroup. In this study, cardiac catheterization was performed in 133 patients with noncritical AS. Doppler echocardiography was 95% accurate in this subgroup. Although most elderly patients do not require cardiac catheterization before aortic valve surgery, they require selective coronary arteriography before aortic valve surgery. Patients in whom Doppler echocardiography shows a peak jet velocity between 3.6 and 4.4 m/sec and an aortic valve area greater than 0.8 cm2 should undergo cardiac catheterization if they have cardiac symptoms attributable to AS (47). Patients with a peak jet velocity between 3 and 3.5 m/sec and a LV ejection fraction less than 50% may have severe AS, requiring aortic valve replacement, and should undergo cardiac catheterization (48). Patients with a peak jet velocity between 3 and 3.5 m/sec and a LV ejection fraction greater than 50% probably do not need aortic valve replacement (AVR) but should undergo cardiac catheterization if they have symptoms of severe AS (48). Natural History Ross and Braunwald (37) found that the average survival rate was three years after the onset of angina pectoris in patients with severe AS. Ross and Braunwald (37) reported that the average survival rate after the onset of syncope in patients with severe AS was three years. Ross and Braunwald (37) demonstrated that the average survival rate after the onset of CHF in patients with severe AS was 1.5 to 2 years. Patients with symptomatic severe valvular AS have a poor prognosis (36–39,52). At the National Institutes of Health, 52% of patients with symptomatic severe valvular AS not operated on were dead at five years (38,39). At 10-year follow-up, 90% of these patients were dead. At four-year follow-up of patients aged 75 to 86 years in the Helsinki Aging Study, the incidence of cardiovascular mortality was 62% in patients with severe AS and 35% in patients with moderate AS (53). At four-year follow-up the incidence of total mortality was 76% in patients with severe AS and 50% in patients with moderate AS (53). In a prospective study, at 19-month follow-up (range, 2–36 months), 90% of 30 patients with CHF associated with unoperated severe AS and a normal LV ejection fraction were dead (33). At 13-month follow-up (range, 2–24 months), 100% of 18 patients with CHF associated with unoperated severe AS and an abnormal LV ejection fraction were dead (33). Table 3 shows the incidence of new coronary events in elderly patients with no, mild, moderate, and severe AS. Independent risk factors for new coronary events in this study were prior myocardial infarction, AS, male gender, and increasing age (36). In this prospective study, at 20-month follow-up of 40 elderly patients with severe AS, CHF, syncope, or angina pectoris was present in 36 of 37 patients (97%) who developed new coronary events and in none of 3 patients (0%) without new coronary events (36). At 32-month follow-up

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Table 3 Incidence of New Coronary Events in Older Persons with No, Mild, Moderate, and Severe Valvular AS No AS (n ¼ 1496) Age (yr) Follow-up (mo) New coronary events

81 49 41%

Mild AS (n ¼ 165) 84 52 62%

Moderate AS (n ¼ 96) 85 32 80%

Severe AS (n ¼ 40) 85 20 93%

Abbreviation: AS, aortic stenosis. Source: Adapted from Ref. 36.

of 96 elderly patients with moderate valvular AS, CHF, syncope, or angina pectoris was present in 65 of 77 patients (84%) who developed new coronary events and in 1 of 19 patients (5%) without new coronary events (36). At 52-month follow-up of 165 elderly patients with mild AS, CHF, syncope, or angina pectoris was present in 40 of 103 patients (39%) who developed new coronary events and in 5 of 62 patients (8%) without new coronary events (36). In a prospective study of 981 patients, mean age 82 years, with aortic sclerosis and of 999 patients, mean age 80 years, without valvular aortic sclerosis, elderly patients with aortic sclerosis had, at 46-month follow-up, a 1.8 times higher chance of developing a new coronary event than those without valvular aortic sclerosis (7). Otto et al. (54) also reported in 5621 men and women aged 65 years or above that AS and aortic sclerosis increased cardiovascular morbidity and mortality. Kennedy et al. (55) followed 66 patients with moderate AS diagnosed by cardiac catheterization (aortic valve area 0.7–1.2 cm2). In 38 patients with symptomatic moderate AS and 28 patients with minimally symptomatic moderate AS, the probabilities of avoiding death from AS were 0.86 for patients and 1.0 for patients with minimally symptomatic moderate AS at one-year follow-up, 0.77 for patients with symptomatic AS and 1.0 for patients with minimally symptomatic AS at two years, 0.77 for patients with symptomatic AS and 0.96 for patients with minimally symptomatic AS at three years, and 0.70 for patients with symptomatic AS and 0.90 for patients with minimally symptomatic AS at four years (55). During 35-month mean follow-up in this study, 21 patients underwent aortic valve replacement. Hammermeister et al. (56) followed 106 patients with unoperated AS in the Veterans Administration Cooperative Study on Valvular Heart Disease for five years. During follow-up, 60 of 106 patients (57%) died. Multivariate analysis demonstrated that measures of the severity of the AS, the presence of CAD, and the presence of CHF were the important predictors of survival in unoperated patients. Studies have demonstrated that patients with asymptomatic severe AS are at low risk for death and can be followed until symptoms develop (57–60). Turina et al. (57) followed 17 patients with asymptomatic or mildly symptomatic AS. During the first two years, none died or had aortic valve surgery. At five-year follow-up, 94% were alive and 75% were free of cardiac events. Kelly et al. (58) followed 51 asymptomatic patients with severe AS. During 17-month follow-up, 21 (41%) of the patients became symptomatic. Only 2 of the 51 patients (4%) died of cardiac causes. In both patients, death was preceded by the development of angina pectoris or CHF. Pellikka et al. (59) observed that 113 of 143 patients (79%), mean age 72 years, with asymptomatic severe AS were not initially referred for AVR or percutaneous aortic balloon valvuloplasty. During 20-month followup, 37 of 113 patients (33%) became symptomatic. The actuarial probability of remaining free of cardiac events associated with AS, including cardiac death and aortic valve surgery,

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was 95% at six months, 93% at one year, and 74% at two years. No asymptomatic person with severe AS developed sudden death while remaining asymptomatic. Rosenheck et al. (60) followed 126 patients with asymptomatic severe AS for 22 months. Eight patients died and 59 patients developed symptoms necessitating aortic valve replacement. Event-free survival was 67% at one year, 56% at two years, and 33% at four years. Five of the six deaths from cardiac disease were preceded by symptoms. Of the patients with moderately or severely calcified aortic valves whose aortic jet velocity increased by 0.3 m/sec or more within one year, 79% underwent AVR or died within two years. When patients with low gradient AS due to abnormal LV ejection fraction are considered for aortic valve replacement, failure to respond to dobutamine and large preoperative LV end-systolic and end-diastolic volumes are poor prognostic signs (61–63). The American College of Cardiology/American Heart Association (ACC/AHA) guidelines state that dobutamine stress echocardiography is reasonable to evaluate patients with low-flow/ low-gradient AS and abnormal LV ejection fraction (64). Medical Management Prophylactic antibiotics are not recommended to prevent bacterial endocarditis in patients with AS regardless of severity, according to AHA guidelines (65). Patients with CHF, exertional syncope, or angina pectoris associated with moderate or severe AS should undergo AVR promptly. Valvular surgery is the only definitive therapy in these elderly patients (64,66). Medical therapy does not relieve the mechanical obstruction to left ventricular outflow and does not relieve symptoms or progression of the disorder. Patients with asymptomatic AS should report the development of symptoms possibly related to AS immediately to the physician. If significant AS is present in asymptomatic elderly patients, clinical examination and an electrocardiogram and Doppler echocardiogram should be performed at six-month intervals. Nitrates should be used with caution in patients with angina pectoris and AS to prevent the occurrence of orthostatic hypotension and syncope. Diuretics should be used with caution in patients with CHF to prevent a decrease in cardiac output and hypotension. Vasodilators should be avoided. Digitalis should not be used in patients with CHF and a normal LV ejection fraction unless needed to control a rapid ventricular rate associated with AF. Aortic Valve Replacement Table 4 lists four class I indications and one class IIa indication for performing AVR in elderly patients with AS (64). AVR is the procedure of choice for symptomatic elderly patients with severe AS. Other class I indications for AVR in elderly patients with severe AS include patients undergoing coronary artery bypass graft (CABG), undergoing surgery Table 4 ACC/AHA Class I Indications for Aortic Valve Replacement in Persons with Severe AS 1. 2. 3. 4. 5.

Patients with symptomatic severe AS Patients with severe AS undergoing coronary artery bypass surgery Patients with severe AS undergoing surgery on the aorta or other heart valves Patients with severe AS and a left ventricular ejection fraction <50% Patients with moderate AS undergoing coronary artery bypass surgery or surgery on the aorta or other heart valves (class IIa indication)

Abbreviations: ACC/AHA, American College of Cardiology/American Heart Association; AS, aortic stenosis Source: Modified from Ref. 64.

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on the aorta or other heart valves, and patients with a LV ejection fraction less than 50% (64). Patients with moderate AS undergoing CABG or surgery on the aorta or other heart valves have a class IIa indication for AVR (64). Although the ACC/AHA guidelines do not recommend AVR in patients with asymptomatic severe AS and normal LV ejection fraction, there are some data suggesting otherwise. (67). Pai et al. (67) found in their database that 99 of 338 patients (29%), mean age 71 years, with asymptomatic severe AS had AVR during 3.5-year follow-up. Survival at one, two, and five years was 67%, 56%, and 38%, respectively, for nonoperated patients and 94%, 93%, and 90%, respectively, for those who had AVR (67). Echocardiography is recommended in asymptomatic patients with AS every one year for severe AS, every one to two years for moderate AS, and every three to five years for mild AS (64). The bioprosthesis has less structural failure in elderly patients than in younger patients and may be preferable to the mechanical prosthetic valve for AS replacement in the elderly because of the anticoagulation issue (68,69). Patients with mechanical prostheses need anticoagulant therapy indefinitely. Patients with porcine bioprostheses may be treated with aspirin in a dose of 75 to 100 mg daily unless the patient has AF, abnormal LV ejection fraction, previous thromboembolism, or a hypercoagulable condition (64,70). Table 5 lists four class I indications and two class IIa indications for antithrombotic therapy in patients with AVR (64). Arom et al. (71) performed AVR in 273 patients aged 70 to 89 years (mean age, 75 years), 162 with AVR alone, and 111 with AVR plus CABG. Operative mortality was 5%. Late mortality at 33-month follow-up was 18%. Actuarial analysis showed at five-year follow-up that overall survival was 66% for patients with AVR alone, 76% for patients with AVR plus CABG, and 74% for a similar age group in the general population. A U.K. heart valve registry observed in 1100 patients aged 80 years or above (56% women) who underwent AVR that the 30-day mortality was 6.6% (72). The actuarial survival was 89% at one year, 79% at three years, 69% at five years, and 46% at eight

Table 5 Class I Indications for Antithrombotic Therapy in Patients with AVR 1. After AVR with bileaflet mechanical or Medtronic Hall prostheses, in patients with no risk factors, administer warfarin to maintain INR between 2.0 and 3.0; if risk factors are present, the INR should be maintained between 2.5 and 3.5. 2. After AVR with Starr-Edwards valves or mechanical disc valves (other than Medtronic Hall prostheses), in patients with no risk factors, warfarin should be administered to maintain INR between 2.5 and 3.5. 3. After AVR with a bioprosthesis and no risk factors, administer aspirin in a dose of 75–100 mg daily. 4. After AVR with a bioprosthesis and risk factors, administer warfarin to maintain an INR between 2.0 and 3.0. 5. During the first 3 months after AVR with a mechanical prosthesis, it is reasonable to give warfarin to maintain an INR between 2.5 and 3.5 (class IIa indication). 6. During the first 3 mo after AVR with a bioprosthesis in patients with no risk factors, it is reasonable to give warfarin to maintain an INR between 2.0 and 3.0 (class IIa indication). Risk factors include atrial fibrillation, prior thromboembolism, left ventricular systolic dysfunction, and hypercoagulable condition. Abbreviations: AVR, aortic valve replacement; INR, international normalized ratio. Source: Modified from Ref. 64.

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years. The survival of patients with severe AS, a LV ejection fraction less than 35%, and a low transvalvular gradient at one year and at four years was 82% and 78%, respectively, in 39 patients, mean age 73 years, who underwent AVR versus 41% and 15%, respectively, in 56 patients, mean age 75 years, in a control group (73). In 242 patients, mean age 83 years, with AS who had AVR, actuarial survival was 92% at one year and 66% at five years (74). Concomitant CABG did not affect late survival (74). Paroxysmal or chronic AF is a risk factor for mortality in patients with severe AS and a LV ejection fraction less than or equal to 35% undergoing AVR (75). Of 83 patients, mean age 70 years, with severe AS and a LV ejection fraction less than or equal to 35%. Among them, 29 (35%) had paroxysmal or chronic AF (75). The perioperative mortality was 24% in the AF group versus 5.5% in the non-AF group ( p ¼ 0.03) (75). AVR is associated with a reduction in LV mass and in improvement of LV diastolic filling (76–78). Hoffman and Burckhardt (79) performed a prospective study in 100 patients who had AVR. At 41-month follow-up, the yearly cardiac mortality rate was 8% in patients with electrocardiographic LV hypertrophy and repetitive ventricular premature complexes two or more couplets per 24 hours during 24-hour ambulatory monitoring and 0.6% in patients without either of these findings (79). If LV systolic dysfunction in patients with severe AS is associated with critical narrowing of the aortic valve rather than myocardial fibrosis, it often improves after successful AVR (80). In 154 patients, mean age 73 years, with AS and a LV ejection fraction less than or equal to 35% who underwent AVR, the 30-day mortality was 9%. The five-year survival was 69% in patients without significant CAD and 39% in patients with significant CAD. New York Heart Association functional class III or IV was present in 58% of patients before surgery versus 7% of patients after surgery. Postoperative LV ejection fraction was measured in 76% of survivors at a mean of 14 months after surgery. Improvement in LV ejection fraction was found in 76% of patients (80). Balloon Aortic Valvuloplasty AVR is the procedure of choice for symptomatic elderly patients with severe AS. In a Mayo Clinic study, the actuarial survival of 50 elderly patients, mean age 77 years, with symptomatic severe AS in whom AVR was refused (45 patients) or deferred (5 patients) was 57% at one year, 37% at two years, and 25% at three years (81). Because of the poor survival in this group of patients, balloon aortic valvuloplasty should be considered when operative intervention is refused or deferred. On the basis of the available data, balloon aortic valvuloplasty should be considered for elderly patients with symptomatic severe AS who are not candidates for aortic valve surgery and possibly for patients with severe LV dysfunction as a bridge to subsequent valve surgery (82–84). Percutaneous Transcatheter Implantation of Aortic Valve Prostheses Percutaneous heart valve implantation may be performed in non-surgical patients with end-stage calcific AS (85,86). Ongoing trials will define the clinical role for this therapy. Eighteen high-risk patients, mean age 76 years, with severe AS and moderate CAD amenable to percutaneous coronary intervention (PCI) had combined PCI followed by minimally invasive AVR (87). One of 18 patients (6%) died postoperatively with no late mortality after a mean follow-up of 19 months (97). This hybrid strategy may be a new therapeutic approach for elderly high-risk patients with combined CAD and severe AS.

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AORTIC REGURGITATION Etiology and Prevalence Acute aortic regurgitation (AR) in elderly patients may be due to infective endocarditis, rheumatic fever, aortic dissection, trauma following prosthetic valve surgery, or rupture of the sinus of Valsalva, and causes sudden severe LV failure. Chronic AR in elderly patients may be caused by valve leaflet disease (secondary to any cause of AS, infective endocarditis, rheumatic fever, congenital heart disease, rheumatoid arthritis, ankylosing spondylitis, following prosthetic valve surgery, or myxomatous degeneration of the valve) or by aortic root disease. Examples of aortic root disease causing chronic AR in elderly patients include association with systemic hypertension, syphilitic aortitis, cystic medial necrosis of the aorta, ankylosing spondylitis, rheumatoid arthritis, Reiter’s disease, systemic lupus erythematosus, Ehler-Danlos syndrome, and pseudoxanthoma elasticum. Mild or moderate AR was also diagnosed by Doppler echocardiography in 9 of 29 patients (31%) with hypertrophic cardiomyopathy (88). Margonato et al. (89) linked the increased prevalence of AR with age to aortic valve thickening. The prevalence of AR increases with age (89–91). In a prospective study of 450 unselected patients, mean age 82 years, AR was diagnosed by pulsed Doppler echocardiography in 39 of 114 men (34%) and in 92 of 336 women (27%) (91). Severe or moderate AR was diagnosed in 74 of 450 elderly patients (16%). Mild AR was diagnosed in 57 of 450 elderly patients (13%). In a prospective study of 924 men, mean age 80 years, and 1881 women, mean age 82 years, valvular AR was diagnosed by pulsed Doppler recordings of the aortic valve in 282 of 924 men (31%) and in 542 of 1881 women (29%) (25). Pathophysiology The primary determinants of AR volume are the regurgitant orifice area, the transvalvular pressure gradient, and the duration of diastole (92). Chronic AR increases LV ventricular end-diastolic volume. The largest LV end-diastolic volumes are seen in patients with chronic severe AR. LV stroke volume increases to maintain the forward stroke volume. The increased preload causes an increase in LV diastolic stress and the addition of sarcomeres in series. This results in an increase in the ratio of the LV chamber size to wall thickness. This pattern of LV hypertrophy is called eccentric LV hypertrophy. Primary myocardial abnormalities or ischemia due to coexistent CAD depress the contractile state. LV diastolic compliance decreases, LV end-systolic volume increases, LV end-diastolic pressure rises, left atrial pressure increases, and pulmonary venous hypertension results. When the LV end-diastolic radius-to-wall thickness ratio rises, LV systolic wall stress increases abnormally because of the preload and afterload mismatch (27,93). Additional stress then decreases the LV ejection fraction response to exercise (94). Eventually, the LV ejection fraction, forward stroke volume, and effective cardiac output are decreased at rest. We demonstrated that an abnormal resting LV ejection fraction occurred in 8 of 25 elderly patients (32%) with CHF associated with chronic severe AR (95). In patients with acute severe AR, the LV cannot adapt to the increased volume overload. Forward stroke volume falls, LV end-diastolic pressure increases rapidly to high levels, (96) and pulmonary hypertension and pulmonary edema result. The rapid rise of the LV end-diastolic pressure to exceed the left atrial pressure in early diastole causes premature closure of the mitral valve (97). This prevents backward transmission of the elevated LV end-diastolic pressure to the pulmonary venous bed.

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Symptoms Patients with acute AR develop symptoms because of the sudden onset of CHF, with marked dyspnea and weakness. Patients with chronic AR may remain asymptomatic for many years. Mild dyspnea on exertion and palpitations, especially on lying down, may occur. Exertional dyspnea, orthopnea, paroxysmal nocturnal dyspnea, fatigue, and edema are common clinical symptoms of LV failure. Syncope is rare. Angina pectoris occurs less often in patients with AR than in patients with AS and may be due to coexistent CAD. However, nocturnal angina pectoris, often accompanied by flushing, diaphoresis, and palpitations, may develop when the heart rate slows and the arterial diastolic pressure falls to very low levels. Most patients with severe AR who do not have surgery die within two years after CHF develops (98). Signs The AR murmur is typically a high-pitched blowing diastolic murmur that begins immediately after A2. The diastolic murmur is best heard along the left sternal border in the third and fourth intercostal spaces when AR is due to valvular disease. The murmur is best heard along the right sternal border when AR is due to dilatation of the ascending aorta. The diastolic murmur is best heard with the diaphragm of the stethoscope with the person sitting up, leaning forward, and holding the breath in deep expiration. The severity of AR correlates with the duration of the diastolic murmur, not with the intensity of the murmur. Grayburn et al. (99) heard an AR murmur in 73% of 82 patients with AR and in 8% of 24 patients without AR. Saal et al. (100) heard an AR murmur in 80% of 35 patients with AR and in 10% of 10 patients without AR. Meyers et al. (101) heard an AR murmur in 73% of 66 patients with AR and in 22% of 9 patients without AR. Table 6 shows that an AR murmur was heard in 95% of 74 elderly patients with severe or moderate AR diagnosed by pulsed Doppler echocardiography, in 61% of 57 elderly patients with mild AR, and in 3% of 319 elderly patients with no AR (91). In patients with chronic severe AR, the LV apical impulse is diffuse, hyperdynamic, and displaced laterally and inferiorly. A rumbling diastolic murmur (Austin Flint) may be heard at the apex, with its intensity decreased by inhalation of amyl nitrite. A short basal systolic ejection murmur is heard. A palpable LV rapid filling wave and an audible S3 at the apex are usually found. Physical findings due to a large LV stroke volume and a rapid diastolic runoff in patients with severe AR include a wide pulse pressure with an increased systolic arterial pressure and an abnormally low diastolic arterial pressure, an arterial pulse that abruptly rises and collapses, a bisferiens pulse, bobbing of the head with each heart beat, booming systolic and diastolic sounds heard over the femoral artery, capillary pulsations, and systolic and diastolic murmurs heard over the femoral artery when compressing it proximally and distally. Table 6 Correlation of Aortic Regurgitation Murmur with Severity of AR in Elderly Patients with Chronic Aortic Regurgitation AR murmur (%) Severe or moderate AR (n ¼ 74) Mild AR (n ¼ 57) No AR (n ¼ 319) Abbreviation: AR, aortic regurgitation. Source: Adapted from Ref. 91.

95 61 3

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Electrocardiography and Chest Roentgenography The electrocardiogram may initially be normal in patients with acute severe AR. Roberts and Day (102) showed in 30 necropsy patients with chronic severe AR that the electrocardiogram did not accurately predict the severity of AR or cardiac weight. Using various electrocardiographic criteria, the prevalence of LV hypertrophy varied from 30% (RV6>RV5) to 90% (total 12-lead QRS voltage >175 mm). The P-R interval was prolonged in 28% of patients, and the QRS duration was greater than or equal to 0.12 seconds in 20% of patients (102). The chest X-ray in patients with acute severe AR may show a normal heart size and pulmonary edema. The chest X-ray in patients with chronic severe AR usually shows a dilated LV, with elongation of the apex inferiorly and posteriorly and a dilated aorta. Aneurysmal dilatation of the aorta suggests that aortic root disease is causing the AR. Linear calcifications in the wall of the ascending aorta are seen in syphilitic AR and in degenerative disease.

Echocardiography and Doppler Echocardiography M-mode and two-dimensional echocardiography and Doppler echocardiography are very useful in the diagnosis of AR. Two-dimensional echocardiography can provide information showing the etiology of the AR and measurements of LV function. Eccentric LV hypertrophy is diagnosed by echocardiography if the LV mass index is increased with a relative wall thickness less than 0.45 (103–105). Echocardiographic measurements reported to predict an unfavorable response to AVR in patients with chronic AR include a LV end-systolic dimension greater than 55 mm (106), a LV shortening fraction less than 25% (106), a LV diastolic radius-to-wall thickness ratio greater than 3.8 (107), a LV enddiastolic dimension index greater than 38 mm/m2 (2,107), and a LV ventricular endsystolic dimension index greater than 26 mm/m2 (2,107). Grayburn et al. (99) showed that pulsed Doppler echocardiography correctly identified the presence of AR in 57 of 57 patients (100%) with greater than or equal to 2þAR and in 22 of 25 patients (88%) with 1þAR. Saal et al. (100) demonstrated that pulsed Doppler echocardiography identified the presence of AR in 34 of 35 patients (97%) with documented AR. Continuous-wave Doppler echocardiography has also been shown to be very useful in diagnosing and quantitating AR (108,109). AR is best assessed by color flow Doppler imaging (110). Figure 6 illustrates two-dimensional echocardiographic and color Doppler findings in an elderly patient with chronic severe AR. Figure 7 illustrates continuous-wave Doppler findings in the elderly patient with chronic severe AR shown in Figure 6.

Natural History The natural history of chronic AR is significantly different from the natural history of acute AR. Patients with acute AR should have immediate AVR because death may occur within hours to days. In one study of patients with hemodynamically significant chronic AR treated medically, 75% were alive at five years after diagnosis (52,111). Of patients with moderate to severe chronic AR, 50% were alive at 10 years after diagnosis (52,111). The 10-year survival rate for patients with mild to moderate chronic AR was 85% to 95% (52,112).

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Figure 6 Two-dimensional echocardiographic image from an apical four-chamber view in an elderly patient with severe aortic insufficiency, showing a large diastolic aliasing color Doppler jet in the left ventricular outflow tract. Abbreviations: AI, aortic insufficiency; LV, left ventricular cavity; MV, mitral valve leaflets; LA, left atrium; RA, right atrium.

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Figure 7 Continuous-wave Doppler recording of the velocity profile across the aortic valve in the same patient shown in Figure 6. A holosystolic decrescendo high-velocity profile is recorded from the left ventricular outflow tract, characteristic of aortic insufficiency. Abbreviation: AI, aortic insufficiency.

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In another study of 14 patients with chronic severe AR who did not have surgery, 13 (93%) died within two years of developing CHF (98). The mean survival time after the onset of angina pectoris is five years (111). During 8-year follow-up of 104 asymptomatic patients with chronic severe AR and normal LV ejection fraction, 2 patients (2%) died suddenly, and 23 patients (22%) had AVR (113). Of the 104 patients, 19 (18%) had AVR because of cardiac symptoms and 4 (4%) had AVR because of the development of LV systolic dysfunction in the absence of cardiac symptoms. Multivariate analysis showed that age, initial end-systolic dimension, rate of change in end-systolic dimension, and resting LV ejection fraction during serial studies predicted the outcome. In a prospective study, at 24-month follow-up (range, 7–55 months) of 17 patients, mean age 83 years, with CHF associated with unoperated severe chronic AR and a normal LV ejection fraction, 15 patients (88%) were dead (95). At 15-month follow-up (range, 8–21 months) of eight patients, mean age 85 years, with CHF associated with unoperated severe chronic AR and an abnormal LV ejection fraction, all of them (100%) were dead (95). Medical and Surgical Management Asymptomatic patients with mild or moderate AR do not require therapy. However, prophylactic antibiotics should be used to prevent bacterial endocarditis in patients with AR, according to AHA guidelines (65). Echocardiographic evaluation of LV end-systolic dimension should be performed yearly if the measurement is less than 50 mm, but at every three to six months if the LV end-systolic dimension is 50 to 54 mm. AVR should also be considered when the LV ejection fraction approaches 50% before the decompensated state (92). Patients with asymptomatic, chronic severe AR have been treated with hydralazine (114), nifedipine (115), or angiotensin-converting enzyme therapy (116) to decrease the LV volume overload. Vasodilator therapy is indicated as chronic therapy in patients with severe AR who have symptoms of an abnormal LV ejection fraction when AVR is not recommended because of additional cardiac or noncardiac factors (class I indication) and as short-term therapy to improve the hemodynamic profile of patients with severe CHF symptoms and severe LV systolic dysfunction before proceeding with AVR (class IIa indication) (64). Long-term vasodilator therapy with enalapril or nifedipine did not reduce or delay the need for AVR in patients with asymptomatic severe AR and normal LV ejection fraction (117). Infections should be treated promptly. Systemic hypertension increases the regurgitant flow and should be treated. Drugs that depress LV function should not be used. Arrhythmias should be treated. Patients with AR due to syphilitic aortitis should receive a course of penicillin therapy. Prophylactic resection should be considered in patients with Marfan’s syndrome when the aortic root diameter exceeds 55 mm (118). Bacterial endocarditis should be treated with intravenous antibiotics. Indications for AVR in patients with AR due to bacterial endocarditis are CHF, uncontrolled infection, myocardial or valvular ring abcess, prosthetic valve dysfunction or dehiscence, and multiple embolic episodes (119–121). CHF should be treated with sodium restriction, diuretics, digoxin if the LV ejection fraction is abnormal, vasodilator therapy, and AVR. Angina pectoris should be treated with nitrates. Patients with acute severe AR should undergo AVR immediately. Patients with chronic severe AR should have AVR if they develop symptoms of CHF, angina pectoris, or syncope (64,113). AVR should also be performed in asymptomatic patients with chronic severe AR if their LV ejection fraction is less than or equal to 50% at rest

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Table 7 ACC/AHA Class I Indications for Aortic Valve Replacement in Persons with Chronic Severe AR 1. Symptomatic patients with severe AR and normal or abnormal LV ejection fraction 2. Asymptomatic patients with severe AR and LV ejection fraction
50% at rest 3. Patients with severe AR undergoing coronary artery bypass surgery or surgery on the aorta or other heart valves 4. Asymptomatic patients with severe AR with LV ejection fraction >50% but a LV end-diastolic dimension >75 mm or a LV end-systolic dimension >55 mm (class IIa indication) Abbreviations: ACC/AHA, American College of Cardiology/American Heart Association; LV, left ventricular; AR, aortic regurgitation. Source: Modified from Ref. 64.

(64,113). Table 7 shows three class I and one class IIa ACC/AHA indications for AVR in patients with chronic severe AR (64). The class I indications for AVR include symptoms with an abnormal or normal LV ejection fraction, no symptoms but a LV ejection fraction less than or equal to 50% at rest, and asymptomatic patients undergoing CABG or surgery on the aorta or other heart valves (64). The class IIa indication for AVR is asymptomatic patients with severe AR with a LV ejection fraction greater than 50% but a LV enddiastolic dimension greater than 75 mm or a LV end-systolic dimension greater than 55 mm (64). Elderly patients undergoing AVR for severe AR have an excellent postoperative survival if the preoperative LV ejection fraction is normal (122–124). If LV systolic dysfunction was present for less than one year, patients also did well postoperatively. However, if the person with severe AR has an abnormal LV ejection fraction and impaired exercise tolerance and/or the presence of LV systolic dysfunction for more than one year, the postoperative survival is poor (122–124). After AVR, women exhibit an excess late mortality, suggesting that surgical correction of severe chronic AR should be considered at an earlier stage in women (125). The operative mortality for AVR in elderly patients with severe AR is similar to that in elderly patients with AVR for valvular AS. The mortality rate is slightly increased in patients with infective endocarditis and in those patients needing replacement of the ascending aorta plus aortic valve replacement. Of 450 patients with severe AR, 273 (61%) had a LV ejection fraction greater than or equal to 50%, 134 (30%) had a LV ejection fraction of 35% to 50%, and 43 patients (10%) had a LV ejection fraction less than 35% (126). The operative mortality was 3.7% for patients with a normal LV ejection fraction, 6.7% for patients with a LV ejection fraction of 35% to 50%, and 14% for patients with a LV ejection fraction less than 35% (126). At 10-year follow-up, survival rates were 70% for patients with a normal LV ejection fraction, 56% for patients with a LV ejection fraction of 35% to 50%, and 41% for patients with a LV ejection fraction less than 35% (126). The bioprosthesis is preferable to the mechanical prosthetic valve for AVR in elderly patients with severe AR as in elderly patients with valvular AS (68,69). Patients with porcine bioprostheses may be treated with antiplatelet therapy alone unless they have AF, abnormal LV ejection fraction, previous thromboembolism, or a hypercoagulable state (64). In a prospective study, AVR in 38 patients with severe AR normalized LV chamber size and mass in two-third of patients undergoing surgery (127). At nine-month follow-up after AVR, 58% of patients had a normal LV end-diastolic dimension, and 50% of patients had a normal LV mass. During further follow-up (18–56 months postoperatively) 66% of patients had a normal LV end-diastolic dimension and 68% of patients had a

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normal LV mass. The LV end-diastolic dimension normalized in 86% of patients with a preoperative LV end-systolic dimension less than or equal to 55 mm. A preoperative LV end-systolic dimension greater than 55 mm was present in 81% of patients with postoperative persistent LV dilatation (127). REFERENCES 1. Roberts WC, Perloff JK, Costantino T. Severe valvular aortic stenosis in patients over 65 years of age. Am J Cardiol 1971; 27:497–506. 2. Waller BF, Roberts WC. Cardiovascular disease in the very elderly. An analysis of 40 necropsy patients aged 90 years or over. Am J Cardiol 1983; 51:403–421. 3. Aronow WS, Schwartz KS, Koenigsberg M. Correlation of aortic cuspal and aortic root disease with aortic systolic ejection murmurs and with mitral anular calcium in persons older than 62 years in a long-term health care facility. Am J Cardiol 1986; 58:651–652. 4. Aronow WS, Kronzon I. Prevalence and severity of valvular aortic stenosis determined by Doppler echocardiography and its association with echocardiographic and electrocardiographic left ventricular hypertrophy and physical signs of aortic stenosis in elderly patients. Am J Cardiol 1991; 67:776–777. 5. Lindroos M, Kupari M, Heikkila J, et al. Prevalence of aortic valve abnormalities in the elderly: an echocardiographic study of a random population sample. J Am Coll Cardiol 1993; 21:1220–1225. 6. Aronow WS, Ahn C, Kronzon I. Association of mitral annular calcium and of aortic cuspal calcium with coronary artery disease in older patients. Am J Cardiol 1999; 84:1084–1085. 7. Aronow WS, Ahn C, Shirani J, et al. Comparison of frequency of new coronary events in older subjects with and without valvular aortic sclerosis. Am J Cardiol 1999; 83:599–600. 8. Roberts WC, Perloff JK. Mitral valvular disease. A clinicopathologic survey of the conditions causing the mitral valve to function normally. Ann Intern Med 1972; 77:939–975. 9. Nair CK, Aronow WS, Stokke K, et al. Cardiac conduction defects in patients older than 60 years with aortic stenosis with and without mitral anular calcium. Am J Cardiol 1984; 53:169–172. 10. Sell S, Scully RE. Aging changes in the aortic and mitral valves. Am J Pathol 1965; 46:345–365. 11. Otto CM, Kuusisto J, Reichenbach DD, et al. Characterization of the early lesion of ‘degenerative’ valvular aortic stenosis. Circulation 1994; 90:844–853. 12. Stewart BF, Siscovick D, Lind BK, et al. Clinical factors associated with calcific aortic valve disease. J Am Coll Cardiol 1997; 29:630–634. 13. Aronow WS, Schwartz KS, Koenigsberg M. Correlation of serum lipids, calcium, and phosphorus, diabetes mellitus and history of systemic hypertension with presence or absence of calcified or thickened aortic cusps or root in elderly patients. Am J Cardiol 1987; 59:998–999. 14. Lindroos M, Kupari M, Valvanne J, et al. Factors associated with calcific aortic valve degeneration in the elderly. Eur Heart J 1994; 15:865–870. 15. Aronow WS, Kronzon I, Schoenfeld MR. Prevalence of extracranial carotid arterial disease and of valvular aortic stenosis and their association in the elderly. Am J Cardiol 1995; 75:304–305. 16. Aronow WS, Ahn C, Kronzon I. Association of valvular aortic stenosis with symptomatic peripheral arterial disease in older persons. Am J Cardiol 2001; 88:1046–1047. 17. Nassimiha D, Aronow WS, Ahn C, et al. Rate of progression of valvular aortic stenosis in persons 60 years. Am J Cardiol 2001; 87:807–809. 18. Nassimiha D, Aronow WS, Ahn C, et al. Association of coronary risk factors with progression of valvular aortic stenosis in older persons. Am J Cardiol 2001; 87:1313–1314. 19. Palta S, Pai AM, Gill KS, et al. New insights into the progression of aortic stenosis. Implications for secondary prevention. Circulation 2000; 101:3497–2502. 20. Roberts WC. The senile cardiac calcification syndrome. Am J Cardiol 1986; 58:572–574. 21. Aronow WS, Schwartz KS, Koenigsberg M. Correlation of serum lipids, calcium and phosphorus, diabetes mellitus, aortic valve stenosis and history of systemic hypertension with presence or absence of mitral anular calcium in persons older than 62 years in a long-term health care facility. Am J Cardiol 1987; 59:381–382.

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65. Wilson W, Taubert KA, Gewitz M, et al. Prevention of infective endocarditis: guidelines from the American Heart Association: a guideline from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee, Council on Cardiovascular Disease in the Young, and the Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and the Quality of Care and Outcomes Research Interdisciplinary Working Group. Circulation 2007; 116:1736–1754. 66. Tresch DD, Knickelbine T. Aortic valvular stenosis in the elderly: a disorder with a favorable outcome if correctly diagnosed and treated. Cardiovasc Rev Rep 1994; 15(7):35–38. 67. Pai RG, Kapoor N, Bansal RC, et al. Malignant natural history of asymptomatic severe aortic stenosis: benefit of aortic valve replacement. Ann Thorac Surg 2006; 82:2116–2122. 68. Hammermeister K, Sethi GK, Henderson WG, et al. Outcomes 15 years after valve replacement with a mechanical versus a bioprosthetic valve: final report of the Veterans Affairs Randomized Trial. J Am Coll Cardiol 2000; 36:1152–1158. 69. Borkon AM, Soule LM, Baughman KL, et al. Aortic valve selection in the elderly patient. Ann Thorac Surg 1988; 46:270–277. 70. Culliford AT, Galloway AC, Colvin SB, et al. Aortic valve replacement for aortic stenosis in persons aged 80 years and older. Am J Cardiol 1991; 67:1256–1260. 71. Arom K, Nicoloff D, Lindsay W, et al. Aortic valve replacement in the elderly: operative risks and long-term results. J Am Coll Cardiol 1990; 15:96A.(abstr). 72. Asimakopoulos G, Edwards MB, Taylor KM. Aortic valve replacement in patients 80 years of age and older. Survival and cause of death based on 1100 cases: collective results from the UK Heart Valve Registry. Circulation 1997; 96:3403–3408. 73. Pereira JJ, Lauer MS, Bashir M, et al. Survival after aortic valve replacement for severe aortic stenosis with low transvalvular gradients and severe left ventricular dysfunction. J Am Coll Cardiol 2002; 39:1356–1363. 74. Unic D, Leacche M, Paul S, et al. Early and late results of isolated and combined heart valve surgery in patients 80 years of age. Am J Cardiol 2005; 95:1500–1503. 75. Levy F, Garayalde E, Quere JP, et al. Prognostic value of preoperative atrial fibrillation in patients with aortic stenosis and low ejection fraction having aortic valve replacement. Am J Cardiol 2006; 98:809–811. 76. Gilchrist IC, Waxman HL, Kurnik PB. Improvement in early diastolic filling dynamics after aortic valve replacement. Am J Cardiol 1990; 66:1124–1129. 77. Villari B, Vassalli G, Monrad ES, et al. Normalization of diastolic dysfunction in aortic stenosis late after valve replacement. Circulation 1995; 91:2353–2358. 78. Kuhl HP, Franke A, Puschmann D, et al. Regression of left ventricular mass one year after aortic valve replacement for pure severe aortic stenosis. Am J Cardiol 2002; 89:408–413. 79. Hoffman A, Burckhardt D. Patients at risk for cardiac death late after aortic valve replacement. Am Heart J 1990; 120:1142–1147. 80. Connolly HM, Oh JK, Orszulak TA, et al. Aortic valve replacement for aortic stenosis with severe left ventricular dysfunction. Prognostic indicators. Circulation 1997; 95:2395–2400. 81. O’Keefe JH Jr., Vlietstra RE, Bailey KR, et al. Natural history of candidates for balloon aortic valvuloplasty. Mayo Clin Proc 1987; 62:986–991. 82. Kuntz RE, Tosteson AN, Berman AD, et al. Predictors of event-free survival after balloon aortic valvuloplasty. N Engl J Med 1991; 325:17–23. 83. Cheitlin MD. Severe aortic stenosis in the sick octogenarian. A clear indicator for balloon valvuloplasty as the initial procedure. Circulation 1989; 80:1906–1908. 84. Rahimtoola SH. Catheter balloon valvuloplasty for severe calcific aortic stenosis: a limited role. J Am Coll Cardiol 1994; 23:1076–1078. 85. Cribier A, Eltchaninoff H, Tron C, et al. Early experience with percutaneous transcatheter implantation of heart valve prosthesis for the treatment of end-stage inoperable patients with calcific aortic stenosis. J Am Coll Cardiol 2004; 43:698–703. 86. Feldman T, Herrmann HC, Goar FS. Percutaneous treatment of valvular heart disease: catheter-based aortic valve replacement and mitral valve repair therapies. Am J Geriatr Cardiol 2006; 15:291–301.

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87. Brinster DR, Byrne M, Rogers CD, et al. Effectiveness of same day percutaneous coronary intervention followed by minimally invasive aortic valve replacement for aortic stenosis and moderate coronary disease (“hybrid approach”). Am J Cardiol 2006; 98:1501–1503. 88. Theard MA, Bhatia SJ, Plappert T, et al. Doppler echocardiographic study of the frequency and severity of aortic regurgitation in hypertrophic cardiomyopathy. Am J Cardiol 1987; 60: 1143–1147. 89. Margonato A, Cianflone D, Carlino M, et al. Frequence and significance of aortic valve thickening in older asymptomatic patients and its relation to aortic regurgitation. Am J Cardiol 1989; 64:1061–1062. 90. Akasaka T, Yoshikawa J, Yoshida K, et al. Age-related valvular regurgitation: a study by pulsed Doppler echocardiography. Circulation 1987; 76:262–265. 91. Aronow WS, Kronzon I. Correlation of prevalence and severity of aortic regurgitation detected by pulsed Doppler echocardiography with the murmur of aortic regurgitation in elderly patients in a long-term health care facility. Am J Cardiol 1989; 63:128–129. 92. Gaasch WH, Sundaram M, Meyer TE. Managing asymptomatic patients with chronic aortic regurgitation. Chest 1997; 111:1702–1709. 93. Ross J Jr. Afterload mismatch and preload reserve: a conceptual framework for the analysis of ventricular function. Prog Cardiovasc Dis 1976; 18:256–264. 94. Greenberg B, Massie B, Thomas D, et al. Association between the exercise ejection fraction response and systolic wall stress in patients with chronic aortic insufficiency Circulation 1985; 71:458–465. 95. Aronow WS, Ahn C, Kronzon I, et al. Prognosis of patients with heart failure and unoperated severe aortic valvular regurgitation and relation to ejection fraction. Am J Cardiol 1994; 74: 286–288. 96. Welch GH Jr., Braunwald E, Sarnoff SJ. Hemodynamic effects of quantitatively varied experimental aortic regurgitation. Circ Res 1957; 5:546–551. 97. Mann T, McLaurin LP, Grossman W, et al. Assessing the hemodynamic severity of acute aortic regurgitation due to infective endocarditis. N Engl J Med 1975; 293:108–113. 98. Massell BF, Amezcua FJ, Czoniczer G. Prognosis of patients with pure or predominant aortic regurgitation in the absence of surgery. Circulation 1966; 34(suppl III):164(abstr). 99. Grayburn PA, Smith MD, Handshoe R, et al. Detection of aortic insufficiency by standard echocardiography, pulsed Doppler echocardiography, and auscultation. A comparison of accuracies. Ann Intern Med 1986; 104:599–605. 100. Saal AK, Gross BW, Franklin DW, et al. Noninvasive detection of aortic insufficiency in patients with mitral stenosis by pulsed Doppler echocardiography. J Am Coll Cardiol 1985; 5:176–181. 101. Meyers DG, Sagar KB, Ingram RF, et al. Diagnosis of aortic insufficiency: comparison of auscultation and M-mode echocardiography to angiography. South Med J 1982; 75:1192–1194. 102. Roberts WC, Day PJ. Electrocardiographic observations in clinically isolated, pure, chronic, severe aortic regurgitation: analysis of 30 necropsy patients aged 19 to 65 years. Am J Cardiol 1985; 55:431–438. 103. Savage DD, Garrison RJ, Kannel WB, et al. The spectrum of left ventricular hypertrophy in a general population sample: the Framingham Study. Circulation 1987; 75(suppl I):26–33. 104. Aronow WS, Ahn C, Kronzon I, et al. Congestive heart failure, coronary events, and atherothrombotic brain infarction in elderly blacks and whites with systemic hypertension and with and without echocardiographic and electrocardiographic evidence of left ventricular hypertrophy. Am J Cardiol 1991; 67:295–299. 105. Koren MJ, Devereux RB, Casale PN, et al. Relation of left ventricular mass and geometry to morbidity and mortality in uncomplicated essential hypertension. Ann Intern Med 1991; 114: 345–352. 106. Henry WL, Bonow RO, Borer JS, et al. Observations on the optimum time for operative intervention for aortic regurgitation. I. Evaluation of the results of aortic valve replacement in symptomatic patients. Circulation 1980; 61:471–483.

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Mitral Regurgitation, Mitral Stenosis, and Mitral Annular Calcification in the Elderly Melvin D. Cheitlin University of California, San Francisco, California, U.S.A.

Wilbert S. Aronow Divisions of Cardiology, Geriatrics, and Pulmonary/Critical Care, Department of Medicine, New York Medical College, Valhalla, New York, U.S.A.

ETIOLOGY Mitral Stenosis The etiology of mitral stenosis (MS) in the elderly as in the young patient is chronic rheumatic heart disease. There is a small incidence of mitral annular calcification with exuberant atherosclerotic encroachment from the annulus into the base of the left ventricle such that the mitral orifice is decreased, producing some degree of mitral stenosis, most often not severe. Reduced anterior leaflet mobility seems to be necessary to produce obstruction sufficient for a gradient of greater than 5 mmHg (1). With the marked decrease in the incidence of acute rheumatic fever in the United States over the last half century, the prevalence of MS in those people under age 40, born and raised in the United States with chronic rheumatic heart disease and MS or mitral regurgitation has markedly decreased, so that MS in this population is seen predominantly in the elderly patient, frequently the older patient who has had earlier mitral valve surgery. Since rheumatic fever is still very common in eastern Europe, Asia, Latin and South America, and Africa, most of the younger patients with MS in the United States were born and raised in these countries. Mitral Regurgitation In the elderly patient mitral valve disease, especially mitral regurgitation (MR), is more frequently seen than aortic valve disease, although aortic stenosis is much more often the reason for valve surgery in this age group (2). MR has numerous etiologies (Table 1) (3). The most frequent etiologies in elderly patients are myxomatous degeneration (mitral 445

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Table 1 Etiologies of MR

1. 2. 3. 4. 5. 6. 7.

8. 9. 10. 11. 12. 13. 14.

Rheumatic heart disease Mitral valve prolapse (myxomatous degeneration)a Infective endocarditisa Left ventricular dilatation (left ventricular failure) Idiopathic rupture of chordae tendinaea Trauma, penetrating and nonpenetratinga Coronary artery disease a. Transient ischemiaa b. Myocardial infarction c. Ruptured papillary musclea Connective tissue diseases (lupus erythematosus, Marfan disease) Mitral annular calcification Postmitral valvotomya Valve dehiscencea Paraprosthetic MR Degeneration of a bioprosthetic valve Drug associated valvulopathy (fenfluoramine, pergolide)

a

Etiologies where clinical picture may be that of acute MR. Abbreviation: MR, mitral regurgitation.

valve prolapse), functional MR due to left ventricular dilatation, coronary artery disease, rheumatic heart disease, and mitral annular calcification. Since mitral annular calcification is seen predominantly in the elderly patient and poses problems beyond those related to volume overload, a detailed discussion of this topic will be presented separately at the end of the chapter. Anorexogenic drugs (fenfluoramine) possibly related to serotonergic medications that are agonists at the 5-hydroxytryptamine (2B) (5-HT 2B) receptor. Have been shown to produce valvulopathy similar to that seen in carcinoid valve disease (4,5). Recently, ergot-derived dopamine receptor agonists (pergolide, cabergoline) often used in Parkinson’s disease have been associated with increased risk of valvular regurgitation (6).

PATHOPHYSIOLOGY MS The major pathology is that of commissural fusion and fusion and shortening of the chordae tendinae. Later, there is increasing fibrosis and calcification of the valve leaflets. Therefore, the obstruction to diastolic flow across the mitral valve can be due to the narrowed mitral orifice caused by commissural fusion and to the thickening and calcification of the leaflets, so that they do not open without a pressure gradient in spite of open commissures or obstruction due to a subvalvular component caused by fused, shortened chordae tendinae. In these latter two instances, commissurotomy will not relieve the obstruction and valve replacement is necessary. The normal mitral valve orifice is approximately 5.0 cm2. With a normal stroke volume there is no obstruction to diastolic flow until the valve area is reduced to approximately 2.0 cm2. When the valve area reaches about 1.0 cm2, there is sufficient

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obstruction at resting flow rates to result in a diastolic gradient across the mitral valve, so the left atrial pressure as well as pulmonary venous and pulmonary capillary pressures rise enough to cause pulmonary congestive symptoms (7). The obstruction and pressure gradient between the left atrium and left ventricle in diastole accelerates the blood through the narrowed orifice, causing the turbulence and vortex formation that generates the characteristic low-frequency diastolic murmur. The loudness of the murmur is related to the magnitude of the pressure gradient and to the volume of blood accelerated across the obstructed valve as well as to the nearness of the chamber in which the murmur is generated (here the left ventricle) to the ear. Since the left ventricular apex pushes the chest wall in systole creating the point of maximal impulse (PMI), this is where the murmur is best heard. As left atrial pressure rises, pulmonary capillary pressure rises and overcomes the colloid osmotic pressure in the pulmonary capillary bed, leading to increasing congestion in the interstitial areas of the lung and finally to pulmonary edema. As left atrial pressure rises, there is a pari passu rise in right ventricular systolic pressure, increasing afterload on the right ventricle, right ventricular hypertrophy, and finally resulting in right ventricular failure. In 10% to 15% of cases there is a marked increase in pulmonary artery pressure and pulmonary vascular resistance due to edema pressure on the interstitial small arteries and vasoconstriction probably mediated by pulmonary artery endothelial release of vasoconstrictive amines such as endothelin. Eventually, with right ventricular failure, there is a decrease in cardiac output, and signs of right ventricular failure with increased central venous pressure, edema, and even ascites (7). As left atrial pressure rises, the left atrium enlarges resulting in atrial fibrillation (AF) that may occur relatively early in the course of MS. With AF, stasis of blood, especially in the left atrial appendage, as well as endocardial changes (8) that promote platelet activation and release of thrombogenic substances result in atrial clotting and form the basis for the high incidence of systemic thromboemboli, the most important of which is embolic stroke that is so common in MS (9). Hemoptysis occurs in these patients as pulmonary venous pressure increases, opening collaterals for run-off to the bronchial veins. These protrude into the lumen of the bronchi and, when rupture occurs, cause hemoptysis (7). Ortner’s syndrome (paralysis of the left vocal cord) can occur with the recurrent laryngeal nerve, which hooks around the ligamentum arteriosus being stretched by the enlarging left pulmonary artery and left atrium (10). MR Mechanism of Regurgitant Orifice Formation The development of MR depends on the formation during systole of a regurgitant orifice. There are a number of mechanisms by which this can occur. Dilatation of the left ventricular OS (including the mitral annulus) is seen in any cause of ventricular failure with left ventricular dilatation. The valve itself remains normal, but the area of the mitral opening is too great to be closed by coaptation of the leaflets. There is also displacement of the papillary muscles and more lateral tension in systole on the leaflet edges, thus restricting leaflet motion (11). A similar problem occurs with ischemia and myocardial fibrosis where the mural leaflet is held from coapting with the anterior leaflet. Other mechanisms of regurgitant orifice formation are loss of leaflet tissue and fibrosis, retraction of leaflet tissue as is seen in rheumatic heart disease, or tearing of the leaflet as in infective endocarditis, seen also in penetrating and nonpenetrating trauma. Finally, there can be loss of infravalvular support as seen in chordal and papillary muscle rupture.

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With myxomatous leaflets, mitral valve prolapse occurs where there may be coaptation of the leaflets early in systole, but as the left ventricle empties and becomes smaller, the redundant leaflet is displaced back above the mitral annulus into the left atrium, and at some point a regurgitant orifice is created (12). With myocardial infarction and fibrosis of the papillary muscle and its origin from the left ventricular wall, as systole progresses, the mitral valve leaflets prolapse toward the left atrium and a regurgitant orifice forms. With annular calcification, the OS of the left ventricle is prevented from constricting during systole and the mural leaflet can be immobilized, preventing it from coapting with the anterior leaflet. Pathophysiology Causing Symptoms Acute MR. The pathophysiology of MR depends on the severity of the leak (regurgitant volume) and the rapidity with which the MR occurred. With sudden chordal or leaflet rupture or valve dehiscence, a sudden low-resistance runoff in systole from the left ventricle develops. If the regurgitant orifice is large, the regurgitant volume will be large. The total left ventricular stroke volume is now divided into the stroke volume going out of the aorta (effective forward stroke volume) and the blood regurgitating back into the left atrium (regurgitant volume). The left ventricle in this situation empties rapidly during systole. Since much of the regurgitant volume goes into the left atrium against low resistance, the left ventricle faces a decreased afterload early in systole, permitting it to empty more easily and achieving a smaller end-systolic volume and a higher ejection fraction (EF) (7). The increased blood coming into the left atrium during systole results in a higher “V” wave. With the next diastole, the blood coming from the pulmonary veins adds to the regurgitant blood thus increasing the left ventricular end-diastolic volume (LVEDV). The Frank–Starling mechanism increases the next left ventricular stroke volume so that the regurgitant volume can be maintained as well as the effective forward stroke volume. In acute MR, the sudden increase in LVEDV, resisted by the unprepared left ventricle and unstretched pericardium, results in a marked rise in left ventricular filling pressure. With the increased filling pressure the left atrial and pulmonary capillary pressure is increased causing pulmonary congestion and pulmonary edema. With the rise in left atrial pressure there is a sudden increase in afterload on the right ventricle, which may dilate and rapidly fail (7). Chronic MR. With gradually increasing regurgitant volume, there is stimulus and time for remodeling of the left ventricle and eccentric hypertrophy to occur. As the ventricle dilates, left ventricular hypertrophy (LVH) occurs so that the wall does not become thinner, preventing an increase in left ventricular wall tension. The ventricle remains compliant and the pericardium stretches to keep the left ventricular filling pressure and the left atrial pressure normal. The dilated more compliant left atrium limits the height of the “V” wave to 30 to 35 mmHg. The left ventricular filling pressure remains normal until the left ventricle fails, at which time the filling pressure rises. Since the left ventricle is contracting against a lower afterload, the EF remains normal or even higher than normal. As the left ventricular end-diastolic diameter increases, eventually the wall tension and afterload increases and the EF begins to fall (13). At this stage, even with the EF still “within normal limits,” there is a decrease in myocardial contractility. When the left atrial mean pressure rises, there is increased afterload on the right ventricle, which eventually leads to right ventricular failure. Here, right ventricular failure is very late in the course of the natural history.

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Age modifies the pathophysiology of MR. In the elderly there is decreased compliance of the left ventricle (14) as well as LVH, which leads to a further, more rapid increase in left ventricular filling pressure given the volume load present in MR. With the increased aortic stiffness present in the elderly (15), there is increased left ventricular impedance to ejection and increased left ventricular afterload leading to earlier decompensation of the left ventricle in MR. CLINICAL PICTURE MS Symptoms For many years, the patient may remain asymptomatic. In the elderly, many patients have had a previous intervention, either surgical or balloon valvotomy. In elderly patients, pulmonary congestion almost always results in progressive dyspnea on exertion and eventually orthopnea and paroxysmal nocturnal dyspnea. Wall tension and enlargement of the left atrium lead to the development of AF and the increased danger of systemic emboli, especially stroke (7). Frequently the first symptoms occur with the onset of AF or, in the young patient, during the course of pregnancy, usually in the late second or third trimester (7). With decreasing right ventricular function, the patient may have fewer symptoms and signs of pulmonary congestion and more problems with decreased exercise tolerance. Eventually, the clinical picture is dominated by the signs and symptoms of right heart failure, pedal edema, engorged neck veins, and finally ascites and the stasis cyanosis of low cardiac output. Signs The murmur of MS is a characteristic low-pitched, rumbling diastolic murmur best heard at the apex. With flexible valve leaflets, the first heart sound is loud and even palpable and there is an opening snap after the S2 in early diastole. The second heart sound may be increased and even palpable if the pulmonary artery pressure is elevated. With severe pulmonary hypertension, a diastolic blowing murmur of pulmonic insufficiency may be heard along the left-sternal border, indistinguishable from the murmur of aortic regurgitation (Graham–Steele murmur). With right ventricular hypertrophy, there may be a precordial lift. With right heart failure, a systolic murmur along the left sternal border of tricuspid regurgitation may be present, as well as an elevated central venous pressure, hepatomegaly, edema, and even ascites (7). Age Modifies Signs and Symptoms of MS In the elderly, symptoms of MS may be far advanced before the patient recognizes them. Elderly patients may accept shortness of breath and decreased exercise tolerance as an inevitable consequence of “getting older.” Also, accompanying comorbidities, such as chronic obstructive pulmonary disease, may be accepted as the cause of the increasing symptoms. In the elderly patient, the antero-posterior (AP) diameter of the chest is frequently increased so that the left ventricle no longer contacts the chest wall. Also, dilatation of the right ventricle may move the left ventricle posteriorly away from contact with the chest wall. Since the low-frequency murmur does not conduct well through the blood of the right ventricle, the murmur may be inaudible (7). Sometimes rolling the patient into the left lateral position can bring the left ventricle into contact with the chest

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wall and make the murmur detectable with the bell of the stethoscope over the point of maximal impulse. Also, increasing the heart rate and cardiac output with exercise increases the diastolic gradient across the mitral valve and makes the murmur louder. Since the elderly are more likely to have a fibrotic, calcified valve, the first heart sound may not be loud and the opening snap may be absent. In these patients the MS may be truly silent and the patient simply looks like a patient of heart failure. Laboratory Findings and Diagnosis The classic findings on a chest X-ray are those of right ventricular dilatation, prominence of the pulmonary artery and pulmonary veins, especially with redistribution to the upper lung fields. There is also a double density behind the right cardiac silhouette protruding beyond the right heart border of left atrial enlargement, and a filling in below the main pulmonary artery segment in the AP view of the left atrial appendage. In the lateral film, at times, calcification of the mitral valve can be seen, but can be observed better on fluoroscopy. The classic findings on electrocardiogram (ECG) are left atrial abnormality and right ventricular hypertrophy. In the elderly, AF is common. The restricted opening of the mitral valve can be seen in the 2-D echocardiogram and the mitral orifice can be planimetered. The increased diastolic velocity across the mitral valve is measured by Doppler echocardiography and the diastolic gradient is calculated by the formula (16) Gradient ¼ 4V2 The severity of the MS can be calculated from the diastolic half-time (17) and the mitral orifice area from the continuity equation (18) Mitral valve area ¼ LV outflow tract area  velocity=Velocity across mitral valve or by the proximal isovelocity surface area (PISA) method (19) Mitral area ¼ Flow ð2r2 Þ=Velocity across mitral valve where r is determined from the Nyquist limit. There are several echocardiographic scores (20,21), which by looking at the thickness and mobility of the leaflets, the degree of leaflet and commissural calcification, and subvalvular chordal fusion, can reliably identify those patients who will benefit from balloon or surgical valvotomy and those who should have valve replacement. Other imaging techniques such as magnetic resonance imaging (MRI) and computed angiographic tomography (CAT) scanning can demonstrate the pathophysiologic abnormalities in MS but generally do not contribute significantly to the more common laboratory studies and therefore are not generally used. MR Symptoms Acute MR. With sudden development of severe MR, there is no time for compensatory eccentric hypertrophy or enlargement of the left atrium, so the patient frequently develops severe shortness of breath, orthopnea, paroxysmal nocturnal dyspnea (PND), early pulmonary edema, and even right heart failure. Since the left atrium is not dilated, it is unusual for the patient to be in AF (22).

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Chronic MR. The patient may remain asymptomatic for years. Eventually the earliest symptom may be a decrease in exercise tolerance rather than dyspnea on exertion since with left ventricular dysfunction the forward stroke volume may decrease with exercise. Later shortness of breath, orthopnea, PND, and left heart failure occur. Finally, right heart failure is very late in the course of the disease (23). The elderly patient may deny symptoms thinking that decreased exercise tolerance is due to aging and shortness of breath is due to pulmonary disease. Also, with a gradual decrease in the patient’s ability to exercise, symptoms may be avoided by decreasing the level of activity so that the patient may have very severe MR and still deny symptoms. Signs Acute MR. With acute MR the perioperative myocardial infarction (PMI) may not be displaced but is hyperactive, especially compared with the radial pulse, and may be rapid rising and abbreviated. If the regurgitant orifice is very large, pressure in the left atrium and left ventricle may approach equality, in which case the murmur may be short or even absent. These patients are usually extremely dyspneic or in pulmonary edema (22). With posterior leaflet prolapse, the regurgitant jet may be directed anteriorly and superiorly so that the murmur may be heard well at the base as well as at the apex. With anterior leaflet prolapse, the jet is directed posteriorly and is well heard in the back. The murmur of acute MR may be confused with that of aortic stenosis but with a premature ventricular contraction, the postextrasystolic beat results in a murmur that does not get louder, unlike that of the postextrasystolic beat in aortic stenosis. With rapid filling of the left ventricle, there is frequently an S3, and since the rhythm is usually sinus rhythm, an S4. Chronic MR. With chronic MR, the left ventricle is dilated and the PMI is displaced laterally and sustained. With the PMI and carotid pulse felt simultaneously, instead of the PMI collapsing before the carotid pulse, with LVH the PMI collapses after the carotid pulse. The pansystolic murmur of MR, best heard at the apex, is flat throughout systole. Since the regurgitation continues throughout all of left ventricular systole, there are no isovolumic contraction or relaxation phases and the murmur classically buries the first and second heart sounds (23). In patients where the regurgitant orifice does not form until the ventricle is ejecting, such as in mitral valve prolapse, nonejection click or clicks may be present as the leaflet prolapses and is suddenly stopped in its motion. Since the regurgitant orifice continues to enlarge as the ventricle empties, the murmur starts after the click, crescendos in loudness, and incorporates the second sound (24). With the marked increase in diastolic blood flow across the mitral valve, there may be a short diastolic rumble and an S3 sound. AF is common in the elderly patient with significant MR. Other signs and symptoms may be related to the etiology of the MR. For instance, with MR secondary to a dilated left ventricle, the findings of cardiomyopathy may be present with an S3 and S4 gallop. Fever and immunoembolic signs may be present in patients with infective endocarditis, physical signs of connective tissue diseases such as Marfan disease, or a history of trauma, angina, or acute myocardial infarction. Laboratory Findings and Diagnosis Chest X-ray. Since there is no time for atrial or ventricular remodeling, in acute MR the heart may not be enlarged on the chest X-ray. Pulmonary congestion and edema are commonly seen. With chronic severe MR, the left atrium and ventricle are dilated and

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appear enlarged on the chest X-ray. With chronic MR, occasionally the left atrium can become extremely dilated so that it touches the right lateral chest wall compressing the right lower lung. ECG. With acute MR, the ECG may be normal, except for sinus tachycardia, or have only nonspecific ST-T-wave changes. With chronic MR, LVH, left atrial abnormality, and AF are common. Echocardiography. The regurgitant volume and size of the regurgitant orifice can be estimated by Doppler echocardiography. The effect of the MR on the size and function of the cardiac chambers can also be evaluated. With acute severe MR, there is frequently pulmonary hypertension, which can be estimated by identifying a tricuspid regurgitant jet that allows estimation of the pulmonary artery systolic pressure (25). The direction of the MR regurgitant jet as well as multiple views on transesophageal echocardiogram (TEE) can reliably show which scallops of the mitral leaflets are prolapsing and define the anatomical and functional mechanism causing the MR; and it is necessary for planning the surgical procedure (26). The severity of MR is more difficult to quantitate than the severity of MS. By Doppler echocardiography, the regurgitant jet by color-flow mapping is composed of a roughly hemispherical area of flow convergence resulting from serial aliasing (PISA), the regurgitant orifice and the fully developed regurgitant jet. Multiple measurements have been used to quantitate the magnitude of MR. The jet area in proportion to the left trial area, the width of the jet at the regurgitant oriface, the calculated regurgitant volume, the intensity of the continuous-wave MR signal, the mitral inflow/pulmonary vein Doppler signs have all been used. Using PISA, it is possible to calculate the regurgitant volume and the effective oriface area. These measurements should be the best estimate of regurgitant severity, although the accuracy of the flow rate by this method depends on many variables such as the shape of the PISA, the oriface geometry, aliasing velocity and others (27). Thomas and colleagues (28) developed an MR index using six echo-Doppler findings, three related to the regurgitant volume and three to the effect on the cardiac chambers. The index correlated well with regurgitant fraction and other measures of MR severity and identified patients with severe MR with a 90% sensitivity, a 88% specificity, and a 79% positive predictive value. As in the case of MS, the imaging techniques of MRI and CAT scanning can demonstrate similar pathophysiologic abnormalities, but are generally not used clinically. NATURAL HISTORY OF MS AND MR IN THE ELDERLY MS A patient over age 65 with MS who has not already had a commissurotomy will have had mild MS for many years, or may have progressed to moderate MS. Others have progressed to severe MS by valvular fibrosis and calcification. Many have had MS diagnosed at an early age and, if symptomatic, had a valvotomy or valve replacement. Once MS becomes symptomatic, the course usually is to become progressively more symptomatic, going through the pulmonary congestive phase, then the right heart failure phase, and finally the low-cardiac-output stage leading to death (7). Since valvotomy or valve replacement has been available for over half a century, it is unusual to see an elderly person with severe MS who has not had at least one attempt at valvotomy.

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Mainly in newly arrived patients in the United States do we see the elderly with previously unrecognized severe MS.

MR The natural history of patients with MR depends on the acuteness of onset, severity, and etiology of MR. The presence of echocardiographic MR early after acute myocardial infarction is predictive of decreased survival. The prevalence of MR increases with age, diabetes, hypertension, and previous revascularization. However, mild or moderate MR may not be an independent prognostic predictor (28). In patients who have decreased ventricular function or heart failure after an acute myocardial infarction, increased MR at baseline was associated with larger LVEDV and left ventricular end-systolic volume, increased sphericity index, and reduced EF. Moderate to severe MR is an independent predictor of total mortality, cardiovascular mortality, and hospitalization for heart failure on follow-up. If the severity of the MR progresses during the first post-myocardial infarction month, patients are likely to die or develop heart failure (29). With MR caused by ischemia or myocardial infarction, the prognosis is poor unless there is minimal myocardial damage and the ischemic muscle can be revascularized and the valve made competent (30). With endocarditis the cause of the MR, the course depends on the infecting organism and the complications seen with infective endocarditis. If trauma is the etiology, the damage to the heart and other organs determines the course. Acute MR How large the regurgitant volume is when the acute MR occurs will determine the symptomatic state of the patient. In the elderly patient, the stiffer left ventricle results in a higher filling pressure for a given volume overload. With a single chord rupture, there may be minimal to moderate regurgitation and the patient may not exhibit the clinical picture of acute MR. With the rupture of several primary chords or of the papillary muscle tip, the patient exhibits the classic clinical picture of acute MR and frequently presents with pulmonary edema, culminating in early demise (22). With the decrease in afterload, the ventricle empties in systole to a greater extent than normal and the EF increases. With myocardial dysfunction, the left ventricular enddiastolic and end-systolic volumes increase and the EF begins to fall, at times into the normal range (13). The decrease in EF in this case still identifies myocardial dysfunction that has a negative effect on prognosis even after surgical correction of the MR (31). Although in one study a relatively high incidence of sudden death has been reported in patients with acute MR due to flail leaflets (32), it has not been confirmed because in that study coronary artery disease could not be ruled out as the etiology. (33). After a period of time, remodeling of the left atrium and left ventricle allows the filling pressure to fall and the effective forward stroke volume to be maintained. The patient may become less symptomatic and the clinical picture may become that of chronic MR. Chronic MR Patients with chronic MR can remain asymptomatic for many years with good exercise tolerance (34). At some point, the volume load on the left ventricle combined with increasing afterload due to the ventricle becoming more spherical and increasing its radius results in myocardial dysfunction. The course becomes that of increasing symptoms and death, usually from congestive heart failure (23).

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TREATMENT OF MS AND MR IN THE ELDERLY MS Balloon Valvotomy for MS In elderly patients with mild-to-moderate MS who have good or acceptable exercise tolerance consistent with their age and not interfering with their life, controlling volume overload, the ventricular rate if in AF, and anticoagulation with warfarin because of the high risk of systemic embolization is the best approach. If the patient develops symptoms that do not respond to gentle diuresis and rate control with b blockers or calcium channel blockers, valvotomy should be considered. If the valve is flexible, with minimal calcification, no left atrial thrombus, and no more than mild (grade 2 or less) MR, the patient is a candidate for valvotomy (35). Commissural calcification has an adverse effect on the results of balloon valvotomy with smaller increases in mitral valve area as calcification increases and a smaller reduction in functional class after balloon mitral valvotomy (36). At the present time with experienced operators, balloon valvotomy is the treatment of choice rather than open commissurotomy (37,38). With balloon valvotomy, the success rate of increasing the valve area to 1.5 cm2 or greater, effectively doubling the valve area, is high—about 90%, even in valves with a high echo score (39). Preexisting MR is a risk factor predicting poor outcome (39,40). The presence of commissural calcium is related to the development of MR after balloon valvotomy, and with calcification of the valve there is less chance that the valve can be opened to greater than or equal to 1.5 cm2 and less improvement in symptoms. Iung and colleagues (41) reported results of balloon valvotomy in 1514 patients, 45  15 years of age. Twenty-five percent had calcified valves. A good result, defined as opening the mitral valve to 1.5 cm2 or more without creating 2 þ or greater MR, was obtained in 1348 (89%) patients. Important predictors of a good result were younger age, echo score less than or equal to 8, and relatively large predilation valve area. Palacios and colleagues (38) reported 327 patients with balloon valvotomy. There were seven inhospital deaths. The follow-up period was 26  12 months. The echo score, which evaluates the anatomical suitability for valvotomy using the Wilkins scoring system (20), was determined. Patients with an echo score greater than 8 compared with those less than or equal to 8 were older (64  11 years vs. 48  14 years) had more AF (65% vs. 40%), more valve calcification (81% vs. 29%) and more previous surgical commissurotomy (30% vs. 16%). Event-free survival was 79  10% for those with echo score less than 8 versus 39  18% with echo score greater than or equal to 8. There is limited experience with valvotomy in patients over ages 60 to 70. Remadi and colleagues (42) reported the immediate and late outcomes of balloon mitral valvotomy in 745 patients, 45 of whom were aged 60 years or older. They compared the immediate and late outcomes with those below 60 years. The baseline hemodynamic parameters were comparable in the two groups as was the degree of mitral valve opening and favorable hemodynamic response. Complication rates, including the development of grade I and II MR, were also similar. After a mean of 43 months of follow-up, a good result was maintained in 60% of patients, even though some degree of restenosis occurred in 40% of the older patients, compared to 25% of the younger patients. Le Feuvre and colleagues (43) reported 234 patients who had a balloon valvotomy, only 28 (10%) aged 70 years or older. Compared to younger patients, the 70 years and older patients had a higher percentage of New York Heart Association (NYHA) class III and IV (84% vs. 67%), and higher echo scores (9.3  2.1 vs. 8.0  1.6), meaning they were less suitable for valvotomy. They also had more AF (61% vs. 36%), more complications (27% vs. 9%),

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Table 2 Long-Term Follow-Up of 532 Patients with Balloon Valvotomy Event-free survival

3 yr

5 yr

7.5 yr

Entire group 84% 74% 52% Age 65 80% 70% 45% Age >65 52% 38% 17% The anatomical form of the mitral valve was the second important factor in event-free survival 3 yr 5 yr 7.5 yr Favorable anatomy (echo score of 1) Intermediate anatomy (echo score of 2) Unfavorable anatomy (echo score of 3)

92%

84%

70%

86%

73%

34%

45%

25%

16%

Source: From Ref. 44.

and a higher 30-day mortality (12% vs. 0.8%). The success rate in opening the valve was similar in both groups. Long-term survival without cardiac events (death, cerebrovascular accidents, another intervention) depends on the patient’s age as well as comorbidity. In general, the older the patient and the more the comorbidity, the shorter the survival. Meneveau and colleagues (44) reported 532 patients after balloon valvotomy (Table 2). The event-free survival was age dependent. The anatomical form of the mitral valve was the second important factor in event-free survival. Given the fact that a calcified valve is unfavorable for valvotomy, in those very symptomatic patients with calcified valves believed to be too great a risk for surgery, balloon valvotomy can be palliative, achieving a moderate increase in valve area at low procedural risk and with improvement of symptoms in the majority of patients. (45). Patients with echo scores that make them unsuitable for balloon valvotomy and rejected for surgery because of frailty or comorbidity can benefit from balloon valvotomy. Sutaria and colleagues (46) reported 80 patients over 70 years of age. Fifty-five were considered unsuitable for surgery. There was a 95% success rate in opening the valve. One year later, 28 of the 55 unsuitable patients (51%) had improved at least one NYHA Class and 14 (25%) at five years. Of the 25 with suitable valves, 16 (64%) had achieved this outcome at one year and 9 (36%) at five years. Shaw and colleagues (47) reported similar results in 20 patients 70 years of age and older. The absence of commissural calcification is a significant predictor of the frequency of achieving a mitral valve opening of 1.5 cm2 without creating severe MR. Sutaria and colleagues (48) reported that calcification of one or more commissures predicts a less than 50% chance of achieving a valve area of greater than or equal to 1.5 cm2. Its influence is greatest in valves with an echo score of less than or equal to 8. Those with commissural calcification grade of 0/1 had a significantly larger number of patients with improvement in symptoms and achieving a valve area of 1.5 cm2 (67%) than those with a grade of 3/4 (46%). (48). If the echo score is greater than 8, the degree of commissural calcification is less important. In patients age 80 and older, there is limited experience of balloon valvotomy. Sutaria and colleagues (49) reported 20 octogenarians (age range 80 to 89) with balloon valvuloplasty, all functional class II to IV, and 14 among them were unfit for surgery. The mitral valve area was increased by 106% from 0.81  0.3 cm2 to 1.67  0.8 cm2. Eight

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patients attained a valve area of greater than or equal to 1.5 cm2 and 16 an area greater than or equal to 1.2 cm2. Eighty percent improved at least one NYHA functional class. Since many elderly patients with MS have had a previous surgical commissurotomy, the question arises whether balloon valvotomy could be successful if restenosis occurs. Iung and colleagues (50) reported the results of balloon valvotomy in 232 patients, mean age 47  14 years, who had undergone a surgical commissurotomy 16  years before. Eighty-one of these patients had valve calcification and bilateral commissural fusion. One patient died (0.4%), MR>2/4 developed in 4% and 82% achieved an immediate valve area of greater than or equal to 1.5 cm2 without significant MR. Predictors of a poor result were age (p < 0.001), smaller initial valve area (p ¼ 0.01), and use of a double-balloon technique (p ¼ 0.015), indicating that results in the elderly would not be as good. In the 175 patients with follow-up, eight-year survival without operation and in NYHA class I and II was 48  5% and in those with good immediate results, 58  6%. The question of whether balloon valvotomy in the patient with MS or in the patient in normal sinus rhythm will prevent the later development of AF addresses the argument that early commissurotomy is necessary this complication. Eid Fawzy and colleagues (51) reported a retrospective analysis of 382 consecutive patients with severe MS in sinus rhythm who had successful balloon valvotomy and were followed for a mean of 5.6 years. Thirty-four (8.9%) patients developed AF compared with 348 (91.1%) who remained in sinus rhythm at follow-up. They compared these results with a reported series in the literature of patients with MS where AF occurred in 29% of patients with similar baseline characteristics who did not have an intervention. The baseline characteristics that were predictive of the late postvalvotomy development of AF were older age, larger left atrium, and a smaller mitral valve area at follow-up. These findings differ from an earlier report by Krasuski and colleagues (52) of a prospective cohort of patients with MS and no history of trial arrhythmias, who showed no decrease in AF after successful versus unsuccessful balloon valvotomy. Advanced age and left atrial dimension were the best predictors of AF at follow-up, whereas procedural success at balloon valvotomy and left trial pressure reduction did not have an impact on the incidence of late AF. Surgical Management of Mitral Valve Disease The surgical management of mitral valve disease in the 65 to 75 age group is not much different than in younger patients, except that older patients have more comorbidity, which increases the mortality and morbidity of surgery. Over age 75 years, there is a marked increase in surgical mortality and morbidity related to limited cardiac, renal, and pulmonary reserves. Since prolongation of life is not as likely in this age group, other therapeutic goals must justify surgery, such as improvement in quality of life (QOL) and return to independent lifestyle. Surgery in an unacceptably symptomatic patient should not be denied on the basis of age alone, and a patient who is symptomatically doing well should not be subjected to surgery with its higher mortality and morbidity. MS Open commissurotomy should be considered when the valve is flexible enough to open when the commissures are released, there is minimal MR, but the subvalvular apparatus is obstructive, when there is thrombus in the left atrium, especially in the body of the left atrium, that remains after two to three months of anticoagulation, which would make

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Table 3 Mitral Commissurotomy Vs. Mitral Valve Replacement Commissurotomy 10-yr survival rate Freedom from reop Freedom from emboli Freedom from hemorrhage

98.7 88.1 93.7 99.3

   

1% 2% 2% 0.5%

Valve replacement 93.7 97.7 83.9 98.4

   

3% 1% 7% 1%

Source: From Ref. 53.

balloon valvotomy hazardous (35). At surgery, the subvalvular structures can be separated, the commissures opened, and the valve preserved. If not, the valve can be replaced. Cotrufo and colleagues (53) reported 540 consecutive MS patients, 340 with mitral commissurotomy and 240 with a bileaflet valve replacement. The majority of patients were less than 65 years of age at the time of surgery. Hospital mortality was 2% in each group (Table 3). With a 15-year follow-up, late mortality was lower in the open commissurotomy group (1%) than in the valve replacement group (3%). With the exception of a greater incidence of reoperation, long-term results were better in the open commissurotomy group. This observation is consistent with many other studies that found that mitral valve repair is preferable to replacement (54,55). With balloon valvotomy available for most patients with MS, the incidence of open commissurotomy has decreased. With the operative technique of preserving the papillary muscle-chordal apparatus in mitral valve replacement, the long-term outcome has approached that of valve commissurotomy. Ismeno and colleagues (56) report 313 patients with isolated MS who received either balloon valvulotomy, open commissurotomy, or valve replacement. (Table 4). There was no difference in operative mortality or seven-year actuarial survival. Freedom from reoperation was significantly better in those with mitral valve replacement and the mean functional class at the end of the follow-up period was lowest in those with open commissurotomy. At present, conservative techniques are the best, especially in the elderly. With the latest operative techniques, the late outcome after mitral valve replacement has markedly improved. MR With the present techniques, most patients with MR (except those with extensive loss of flexible leaflet tissue) can have the valve repaired successfully, but the selection of patients and the expertise of the surgeon are critical factors for success (55). MR due to Table 4 Outcome of MS Intervention

Number 7-yr survival (%) Freedom from emboli (%) Freedom from reop (%) NYHA class at follow-up

BV

OC

VR

111 95.4 95.8 84.4 1.39

82 95.1 98.8 96.4 1.14

120 92.8 92.5 97.7 1.41

(p (p (p (p

¼ > > ¼

NS) 0.05) 0.05) 0.001)

Abbreviations: BV, balloon valvulotomy; OC, open commissurotomy; VR, valve replacement; NS, not significant. Source: from Ref. 56.

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rheumatic heart disease is characterized by fibrosis and retraction of the leaflet edges as well as chordal shortening and fusion (57). Repair is least successful in this group and selection of the proper patients for repair is essential (57). Most MR in the elderly is caused by myxomatous redundant leaflets, and these are ideal candidates for valve repair. With ischemic MR or a dilated left ventricle and left ventricular OS, annuloplasty, with or without an annular ring, is frequently sufficient to create a competent valve (58). However, restricted leaflet motion can make the repair less predictable. Contraindications for repair are loss of leaflet area, extreme leaflet thickening, or calcification of leaflets or commissures (57). Some surgeons have suggested that calcification of the annulus or leaflets does not preclude successful valve repair (59). Grossi and colleagues (60) reported the results of mitral valve repair in 558 patients. Debridement of calcification in annulus and/or leaflets was necessary in 64 (11.5%) patients. Freedom from reoperation at 10 years was 88.1% for debrided patients and 82.6% for those not needing debridement. When good annulus and leaflet mobility can be achieved in calcified valves, calcium debridement allows durable valve repair. Patients with a small mitral annulus or multiple leaflet defects have a small probability of being successfully repaired. Patients with small left ventricular cavities, most often seen in elderly women, have a high incidence of postoperative systolic anterior motion and left ventricular outflow tract obstruction (55). Patients with mitral valve prolapse involving the posterior leaflet have the most success with repair. However, recently, there have been reports of successful repair of anterior leaflet prolapse (61,62) For the best results, patient needs a careful evaluation by TEE and an experienced surgeon. Because the expected lifespan after surgery is shorter for the elderly patient at the time of surgery, there is an advantage of bioprosthetic valves over mechanical valves in older patients since anticoagulation is not necessary in the absence of AF. The frequency of AF in elderly patients with moderate-to-severe chronic MR lessens the advantage because these patients require anticoagulants to prevent systemic emboli (35). There is evidence that valve degeneration occurs much more slowly in the elderly than in younger patients. In one study, the rate of primary structural deterioration in patients over age 65 years was 0.95% per patient-year (63). For this reason, in patients over 65 years of age, the preferred valve is a bioprosthetic one. Dalrymple-Hay and colleagues (54) reported 329 patients with MR due to myxomatous degeneration, mean age 65.5 years with valve repair in 169 and valve replacement in 160 patients. Operative mortality occurred in four (1.2%), all in those with valve replacement. Actuarial survival at 1, 5, and 10 years was 94  1.4%, 77  2.9%, and 41  5.8%, with survival in patients with repair significantly better (p < 0.05) than with valve replacement. Reoperation was required in 10 (6%) of those with valve repair and in 13 (8%) of those with valve replacement. Increased age, worse left ventricular function, the type of operation (repair vs. replacement), and left ventricular size all were significantly associated with poorer survival. Gogbashian and colleagues (64) reported a 10-year experience of mitral valve repair versus replacement in 292 patients aged 70 years and over for MR due to mitral valve prolapse, including patients with concomitant revascularization. Comparing repair to replacement, in-hospital mortality was higher (0.7% vs. 13.9%), length of hospital stay longer (8.7 vs. 9.6 days), and with greater five-year survival (81% vs. 63%). The 10-year freedom from valve reoperation in the patients with repair was 93.9% and for repair plus coronary bypass surgery 98.2%. They concluded that the preferred option for elderly patients was mitral valve repair.

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Lee and colleagues (65) reported 614 patients with valve surgery for severe MR, 190 aged 70 and older and 424 under age 70. In the older patients, there was significantly more myxomatous disease, coronary disease, worse left ventricular function, and worse NYHA class III to IV symptoms. Operative mortality in both young and old patients was low (3.5% vs. 3.7%). In the older patients, seven-year survival was lower than in the young (49  6% vs. 72  3%) as were overt heart failure (74  3% vs. 44  7%) and complication-related deaths (78  3% vs. 57  7%). However, both young and old patients who were NYHA class I with an EF greater than 40% had the same freedom from complication-related death (93  3% in the younger vs. 90  7% in the elderly). These findings support the approach to early surgery once symptoms occur and before the EF begins to fall, especially if valve repair is possible. There is good evidence that valve repair or replacement for MR improves the QOL. Goldsmith and colleagues (66), in a prospective study of 61 consecutive patients with severe MR, mean age 64  12 years, who had mitral valve repair (40) or replacement (21) obtained QOL scores using the short form 36-questionnaire before and three months after surgery. There was significant improvement in seven out of eight QOL parameters in those with repair and in three out of eight in those with valve replacement. Patients with EF greater than or equal to 50% improved in seven out of eight parameters. Those with impaired function or end-systolic dimensions of greater than or equal to 45 mm showed no improvement in any of the parameters. These findings support the importance of early surgery before a decline in left ventricular function. Grossi and colleagues (67) studied 278 patients with mitral valve repair aged 70 and older (mean age 75.2 years). Concomitant procedures were done in 72.3%, with over half having coronary revascularization. Mortality was lower in those with isolated mitral valve repair than in those with concomitant revascularization (6.5% vs. 17%). With an additional valve procedure, the mortality was 13.2%. Long-term survival was excellent with freedom from cardiac death in 100% of those with isolated mitral valve repair, lower in those with a concomitant procedure (79.7%; p ¼ 0.006), and freedom from reoperation in 91.2% patients. Surgery for MR in octogenarians is usually reserved for patients who are very symptomatic despite optimal medical management. There is evidence of recent improvement in the results of surgery for MR in these elderly patients. DeTaint and colleagues (68) reported the results of surgery for MR performed from 1980 to 1995 in patients greater than or equal to 75 years of age (group 1), 65–75 (group 2), and less than 65 (group 3). Preoperatively, Group 1 patients had a higher prevalence of Functional Class III–IV symptoms, more AF and coronary disease, increased creatinine, and higher comorbidity index. The temporal trend of operative mortality showed a decrease in each age group from 27% to 5% in Group 1, 21% to 4% in Group 2, and 7% to 2% in Group 3. Over time, the feasibility of valve repair also increased, in all Groups from 30% to 54%, and in those with degernerative MR (mitral valve prolapse) from 31% to 93%. Multivariate analysis of relative survival showed no difference in restoration of life expectancy compared with younger patients (Table 5). Recent improvements in surgery have benefited elderly patients who should be carefully considered for surgery before refractory heart failure is present. Present guidelines (35) recommend that surgery may be postponed safely in asymptomatic patients with severe MR, even if repair is possible, until the patient develops symptoms or AF, evidence of left ventricular dysfunction with EF falling below 60%, or LVESD increases to 45 mm, or pulmonary hypertension becomes greater than 50 mmHg at rest or greater than 60 mmHg with exercise. Rosenheek and colleagues (34)

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Table 5 Long-Term Survival After Surgery For MR

Number 5-yr survival Rate of observed/expected survival (for age)

Gr 1

Gr 2

Gr 3

284 57  3% 83%

504 73  2% 85%

556 85  2% ( p < 0.001) 88% (p ¼ NS)

Abbreviations: MR, mitral regurgitation; NS, not significant. Source: From Ref 68.

reported 132 such patients 55  15 years of age with severe MR due to mitral valve prolapse or flail leaflet. They underwent serial clinical and echocardiographic monitoring and were followed prospectively for 62  26 months. They were referred for surgery for the above criteria. Only 30% of patients needed surgery by five years and fewer than half by eight years. Symptoms were the commonest indication for surgery. There was no operative mortality and the postoperative outcome was good with regards to survival, symptomatic status and late left ventricular function. Valve replacement is performed in more elderly patients for aortic valve than for mitral valve disease, most often calcific aortic stenosis, and operative mortality is lower than with mitral valve replacement (69,70). Helft and colleagues (63) reported 110 patients, 65 and older (mean 73.4 years), with bioprosthetic valve replacement, 71 with aortic, 32 with mitral, and seven with both. Follow-up was 8.5 years. At five years the actuarial survival was 79.6% and at 10 years 62.4%. Of the 44 patients who died, over half (52.3%) died from non-valve–related causes. Reoperation was needed in 13 patients (11.8%), 10 for structural deterioration, with one death (7.7%). Anticoagulation for AF was needed in 26%, with 6.4% developing severe bleeding (2.9% per patient-year). Similar results have been reported in octogenarians (71–73). In examining the reasons for a higher mortality in octogenarians with MR surgery compared to aortic valve surgery, it is probable that the higher mortality is related more to the patients’ preoperative clinical state and comorbidities than to the type of surgery (71). With MR due to ischemia, operative and late mortality is higher than with MR due to myxomatous degeneration (30). Operative mortality is also higher when the EF is 30% or lower. Hausmann and colleagues (30) reported 337 patients with ischemic MR and mitral valve repair or replacement (Table 6). The goal of surgery in patients with ischemic MR is to reduce the MR to no more than grade 1. Table 6 Surgery for Ischemic MR Op Mort With EF Type of operation Valve repair Valve replace When MR reduced

n

Op mort

10–30%

>30%

140 12.1% 33.3% 8.4% 197 14.2% 30.3% 11.0% to grade 0–1 patient survival best

Abbreviations: Op mort, Operative mortality; EF, ejection fraction. Source: From Ref. 30.

Actuarial survival rate 2 yr

5 yr

7 yr

75.4% 78.6% 81.0%

66.8% 73.4% 78.4%

61.7% 67.2% 77.2%

Figure 16.6 Two-dimensional echocardiographic image from an apical four-chamber view in an elderly patient with severe aortic insufficiency, showing a large diastolic aliasing color Doppler jet in the left ventricular outflow tract. Abbreviations: AI, aortic insufficiency; LV, left ventricular cavity; MV, mitral valve leaflets; LA, left atrium; RA, right atrium.

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Figure 16.7 Continuous-wave Doppler recording of the velocity profile across the aortic valve in the same patient shown in Figure 16.6. A holosystolic decrescendo high-velocity profile is recorded from the left ventricular outflow tract, characteristic of aortic insufficiency. Abbreviation: AI, aortic insufficiency.

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Figure 17.6 Color Doppler echocardiographic findings in a patient with mitral annular calcium and severe MR. Abbreviations: LA, left atrium; RA, right atrium; RV, right ventricle; LV, left ventricle; MR, mitral regurgitation.

Figure 19.11 Color Doppler flow display from a patient with obstructive hypertrophic cardiomyopathy shows turbulent flow in the LVOT and mild mitral regurgitation (MR). Abbreviation: LVOT, left ventricular outflow tract.

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A frequent problem with ischemia and 1 to 3 þ MR is whether to simply revascularize the patient or also make the mitral valve more competent, usually with a annuloplasty. Grossi and colleagues (74) in evaluating the impact of moderate MR in patients undergoing isolated coronary surgery followed 2242 consecutive patients with no to moderate MR. They found that, independent of ventricular function, that mild to moderate MR is associated with significantly decreased survival. Tolis and colleagues (75) had 49 patients, mean age 66.3 years with advanced ischemic heart disease, 1 to 3 þ MR (62% had 2–3 þ MR), and an EF of 10% to 30% (mean 22.4%). In-hospital mortality was 2% and the mean degree of MR went from 1.73 down to 0.54 (p < 0.05). The NYHA class decreased from 3.3 to 1.8 (p < .05) and the EF rose from 22% to 31.5% (p < 0.05). The one-, three-, and five-year survivals were 88%, 65%, and 50%. They concluded that in such patients revascularization was sufficient and that improvement in MR and EF occur from improved left ventricular function and size after revascularization. Aklog and colleagues (58) reported 136 patients, mean age 70.5 years with ischemic heart disease and more severe 3 þ MR with a mean EF of 38.1%. Operative mortality was 2.9%. They found the intraoperative TEE underestimated the degree of MR and the postoperative TTE revealed that 40% of the patients still had 3 þ MR, 51% improved to 2 þ MR, and only 9% had 0 to 1 þ MR. They concluded that ischemic MR required more than just revascularization, usually concomitant annuloplasty. Campwala and colleagues (76) reported the fate of MR following surgical revascularization in 523 patients, 92 of whom had 3 to 4 þ MR on preoperative echocardiogram. Post surgery, residual 3 to 4 þ MR was present in 43 (47%) patients and was associated with a trend to increased mortality ( p ¼ 0.3) over a mean follow-up of 3.9 years. Other studies have reported benefit in terms of symptoms and improved survival in patients with severe left ventricular dysfunction and MR (77), not only due to coronary artery disease but also in patients with cardiomyopathy and chronic valvular regurgitation (78,79).

MITRAL ANNULAR CALCIFICATION Mitral annular calcium (MAC) is a chronic degenerative process that is common in elderly persons, especially women. The amount of calcium may vary from a few spicules to a large mass behind the posterior cusp, often extending to form a ridge or ring encircling the mitral leaflets, occasionally lifting the leaflets toward the left atrium. Sphincter function loss of the mitral annulus and mechanical stretching of the mitral leaflets can cause improper coaptation of the leaflets during systole, resulting in MR (62). Although the calcific mass may immobilize the mitral valve, actual calcification of the leaflets is rare. In persons with severe MAC, the calcification may extend inward to involve the underside of the leaflets. MS may result from severe calcific deposits within the mitral annulus protruding into the orifice (1). Calcific deposits may extend from the mitral annulus into the membranous portions of the ventricular septum, involving the conduction system and causing rhythm and conduction disturbances (80). Although the annular calcium is covered with a layer of endothelium, ulceration of this lining can expose the underlying calcific deposits, which may serve as a nidus for platelet-fibrin aggregation and subsequent thromboembolic episodes (81,82). In patients with endocarditis associated with MAC, the avascular nature of the mitral anulus predisposes to perianular and myocardial abscesses (83,84).

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Table 7 Prevalence of MAC with Increasing Age in Elderly Men and Elderly Women MAC Men

Women

Age (yr)

n

%

n

%

62–70 71–80 81–90 91–100 101–103

4/22 13/42 44/75 19/22 —

18 31 59 86 —

7/35 40/116 146/226 56/63 3/3

20 34 65 89 100

Abbreviation: MAC, Mitral Annular Calcium. Source: Adapted from Ref. 87.

Prevalence MAC is a degenerative process that increases with age and occurs more frequently in women than in men (82,85). In a prospective study of 1797 unselected elderly persons in a long-term health-care facility, mean age 81  8 years (range 60 to 103 years), with technically adequate M-mode and two-dimensional echocardiograms of the mitral valve, MAC was present in 665 of 1243 women (53%) and in 194 of 554 men (35%) (86). Table 7 shows the prevalence of MAC with increasing age in elderly men and elderly women (87). Predisposing Factors Because calcific deposits in the mitral annulus, in the aortic valve cusps, and in the epicardial coronary arteries are commonly associated in elderly persons and have similar predisposing factors, Roberts (88) suggested that MAC and aortic cuspal calcium are a form of atherosclerosis. MAC and aortic cuspal calcium may coexist (80,82,85,88–90). Breakdown of lipid deposits on the ventricular surface of the posterior mitral leaflet at or below the mitral annulus and on the aortic surfaces of the aortic valve cusps is probably responsible for the calcification (80). Increased left ventricular systolic pressure due to aortic valve stenosis increases stress on the mitral apparatus and may accelerate development of MAC (80,82,91). Tricuspid annular calcium and MAC may also coexist and have similar predisposing factors (92). Systemic hypertension increases with age and predisposes to MAC (80,82,83,85,86). Persons with diabetes mellitus also have a higher prevalence of MAC than nondiabetic persons (80,89,90). MAC occurs in the teens with serum total cholesterol levels greater than 500 mg/dL (93). Waller and Roberts (94) suggested that hypercholesterolemia predisposes to MAC. The prevalence of hypercholesterolemia with serum total cholesterol greater than 200 mg/dL was higher in elderly persons with MAC than in elderly persons without MAC (90). Roberts (88) also stated that MAC is rare in older persons residing in areas of the world where serum total cholesterol levels are less than 150 mg/dL. However, Nair and colleagues (89) found no significant difference in mean serum total cholesterol levels between persons younger than 60 years with MAC and a control group. Yetkin and colleagues (95) reported 484 consecutive patients, mean age 60  10, undergoing coronary arteriography for suspected coronary artery disease. Twenty percent of them had MAC. There were no statistically significant differences between those with

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and without MAC with respect to body mass index, diabetes mellitus, hypercholesterolemia, or the presence of coronary artery disease. Roberts and Waller (96) found that chronic hypercalcemia predisposes to MAC. Patients undergoing dialysis for chronic renal insufficiency have an increased prevalence of MAC (96,97). MAC has also been found to be a marker of left ventricular dilatation and decreased left ventricular systolic function in patients with end-stage renal disease on peritoneal dialysis (98). Fox and colleagues (99) studying 3047 participants in the Framingham study of patients with chronic kidney disease, defined by a glomerular filtration rate less than 60 ml/min/1.73 m2, found that the odds of having MAC was increased by 60% in those with chronic kidney disease. Nair and colleagues (89) demonstrated a similar mean serum calcium, a higher mean serum phosphorus, and a higher mean product of serum calcium and phosphorus in patients younger than 60 years with MAC than in a control group. However, Aronow and colleagues (90) observed no significant difference in mean serum calcium, serum phosphorus, or product of serum calcium and phosphorus between elderly persons with and without MAC. By accelerating the rate of rise of left ventricular systolic pressure, hypertrophic cardiomyopathy predisposes to MAC (80). Kronzon and Glassman (100) diagnosed MAC in 12 of 18 patients (67%) older than 55 years with hypertrophic cardiomyopathy and in 4 of 28 patients (14%) younger than 55 years with hypertrophic cardiomyopathyMotamed and Roberts (101) demonstrated MAC in 30 of 100 autopsy patients (30%) with hypertrophic cardiomyopathy older than 40 years and in none of 100 autopsy patients (0%) younger than 40 years with hypertrophic cardiomyopathy. Aronow and Kronzon (102) diagnosed MAC in 13 of 17 older persons (76%) with hypertrophic cardiomyopathy and in 176 of 362 older persons (49%) without hypertrophic cardiomyopathy. Elderly men and women with MAC have a higher prevalence of coronary artery disease (103–105), of peripheral arterial disease (105,106), of extracranial carotid arterial disease (ECAD) (105,107,108), and of aortic atherosclerotic disease (105) than elderly men and women without MAC. MAC has also been shown to be associated with thoracic aorta calcium in patients with systemic hypertension (109). Diagnosis Calcific deposits in the mitral annulus are J, C, U, or O-shaped and are visualized in the posterior third of the heart shadow (82,110,111). MAC may be diagnosed by chest X-ray films or by fluoroscopy (111). However, the procedures of choice for diagnosing MAC are M-mode and two-dimensional echocardiography. Posterior MAC (Fig. 1) is diagnosed by M-mode echocardiography when a band of dense echoes is recorded anterior to the left ventricular posterior wall and moving parallel with it (112). These echoes end at the atrioventricular junction and merge with the left ventricular posterior wall on echocardiographic sweep from the aortic root to the left ventricular apex. Anterior MAC (Fig. 1) is diagnosed by M-mode echocardiography when a continuous band of dense echoes is observed at the level of the anterior mitral leaflet in both systole and diastole (112). These echoes are contiguous with the posterior wall of the aortic root. Calcification may extend from the mitral annulus throughout the base of the heart and into the mitral and aortic valves. Figures 2 and 3 are two-dimensional echocardiograms showing increased echogenicity and brightness of the mitral annulus characteristic of MAC. Using multiple echocardographic views, MAC may be classified as mild, moderate, or severe (113). The echo densities in mild MAC involve less than one-third of the annular circumference

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Figure 1 M-mode echocardiogram with scan from the aortic root to the left ventricular apex in a patient with both anterior and posterior mitral annular calcium. Abbreviations: AOC, aortic calcium; AMAC, anterior mitral annular calcium; PMAC, posterior mitral annular calcium.

Figure 2 Two-dimensional echocardiogram long-axis view depicting MAC. Abbreviations: LA, left atrium; LV, left ventricle; RV, right ventricle; AO, aorta; AML, anterior mitral leaflet; MAC, mitral annular calcium.

(<3 mm in width) and are usually restricted to the angle between the posterior leaflet of the mitral valve and the left ventricular posterior wall. The echo densities in moderate MAC involve less than two-thirds of the annular circumference (3–5 mm in width). The echo densities in severe MAC involve more than two-thirds of the annular circumference

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Figure 3 Two-dimensional echocardiogram four-chamber view of a patient with MAC. Abbreviations: LA, left atrium; RA, right atrium; RV, right ventricle; LV, left ventricle; AML, anterior mitral leaflet; PML, posterior mitral leaflet; MAC, mitral annular calcium.

(>5 mm in width), usually extending beneath the entire posterior mitral leaflet with or without making a complete circle. In a blinded prospective study, MAC was diagnosed by M-mode and twodimensional echocardiography in 55% of 604 unselected elderly patients in a long-term healthcare facility (111). The diagnosis of MAC by chest X-ray films using a lateral chest X-ray in addition to the posterior-anterior or anterior posterior chest X-ray had a sensitivity of 12%, a specificity of 99%, a positive predictive value of 95%, and a negative predictive value of 47%. Patients with radiographic MAC were more likely than patients without radiographic MAC to have a more severe form of the disease, with significant MR, functional MS, or conduction defects. However, patients with echocardiographically severe MAC and significant MR, functional MS, or conduction defects may have no evidence of MAC on chest X-ray films. Figure 4 shows C-shaped calcification of the mitral annulus. Figure 5 illustrates J-shaped calcification of the mitral annulus. Chamber Size Patients with MAC have a higher prevalence of left atrial enlargement (80,83,85,87,89, 113) and left ventricular enlargement (85,89,113) than patients without MAC. In a prospective study of 976 elderly patients (526 with MAC and 450 without MAC), left atrial enlargement was 2.4 times more prevalent in patients with MAC than in the group without MAC (83). AF Patients with MAC also have a higher prevalence of AF than patients without MAC (82,83,85,87,113,114). Table 8 shows that the prevalence of AF was increased 12, 5, and 2.8 times in patients with MAC than in patients without MAC (85,89,114).

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Figure 4 Posterior-anterior chest X-ray in a patient with C-shaped calcification of the mitral annulus (arrows).

Conduction Defects Because of the close proximity of the mitral annulus to the atrioventricular node and the bundle of His, patients with MAC have a higher prevalence of conduction defects, such as sinoatrial disease, atrioventricular block, bundle branch block, left anterior fascicular block, and intraventricular conduction defect, than patients without MAC (81,82,91,113). The calcific deposits may also extend into the membranous portions of the interventricular septum involving the conduction system, or may even extend to the left atrium, interrupting interatrial and intra-atrial conduction. In addition, MAC may be associated with a sclerodegenerative process in the conduction system. Nair et al. (113) showed in

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Figure 5 Posterior-anterior chest X-ray in a patient with J-shaped calcification of the mitral annulus (arrow).

their prospective study that patients with MAC had a higher incidence of permanent pacemaker implantation because of both atrioventricular block and sinoatrial disease than patients without MAC. MR MAC is thought to generate systolic murmurs by the sphincter action loss of the annulus and the mechanical stretching of the mitral leaflets causing MR and from vibration of the

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Table 8 Prevalence of Atrial Fibrillation in Patients With and Without MAC Atrial fibrillation MAC

Framingham Study (85) Patients younger than 61 yr (89) Patients older than 60 yr (mean age 81 þ 8 yr) (114)

No MAC

n

%

n

%

Relative risk

20/162 11/107

12 10

53/5532 2/107

1 2

12 5

225/1028

22

85/1120

8

2.8

Abbreviation: MAC, mitral annular calcium.

Table 9 Prevalence of Apical Systolic Murmurs of MR in Patients with MAC Prevalence of MR murmur

Korn et al. (115) Schott et al. (116) Fulkerson et al. (82) Savage et al. (85) Nair et al. (89) Aronow et al. (117) Aronow et al. (118)

n

%

14/14 10/14 72/80 26/132 17/104 129/293 43/100

100 71a 90 12 16 44 43

a

MAC due to noninflammatory calcific disease. Abbreviations: MR, mitral regurgitation; MAC, mitral annular calcium.

Table 10 Prevalence of MR Diagnosed by Doppler Echocardiography in Patients with MAC MR

Labovitz et al. (120) Aronow et al. (118) Kaul et al. (119) Aronow et al. (114)

Moderate-to-severe MR

n

%

N

%

28/51 54/100 28/29 —

55 54 97a —

17/51 18/100 — 24/1028

33 18 — 22

a

Severe MR in 2 of 29 patients (7%). Abbreviations: MR, mitral regurgitation; MAC, mitral annular calcium.

calcified ring or vortex formation around the annulus. Table 9 shows that the prevalence of apical systolic murmurs of MR in patients with MAC ranged from 12% to 100% in different studies (82,85,89,115–118). Table 10 states the prevalence of MR diagnosed by Doppler echocardiography in patients with MAC (114,118–120). The prevalence of MR associated with MAC ranged from 54% to 97% in the Doppler echocardiographic studies (118–120). Figure 6 illustrates severe MR due to MAC diagnosed by color Doppler echocardiography.

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Figure 6 Color Doppler echocardiographic findings in a patient with mitral annular calcium and severe MR. (See color insert). Abbreviations: LA, left atrium; RA, right atrium; RV, right ventricle; LV, left ventricle; MR, mitral regurgitation.

The greater the severity of MAC, the greater is the severity of MR associated with MAC. Moderate-to-severe MR was diagnosed by Doppler echocardiography in 33% of 51 patients with MAC by Labovitz and colleagues (120) and in 22% of 1028 patients with MAC by Aronow and colleagues (114). Kaul and colleagues (119) diagnosed severe MR in 7% of their 29 patients with MAC, and concluded that MR in patients with MAC is caused by a reduced sphincteric action of the mitral annulus, with MAC preventing the posterior annulus from contracting and assuming a flatter shape during systole. MS An apical diastolic murmur may be heard in patients with MAC as a result of turbulent flow across the calcified and narrowed annulus (annular stenosis). Table 11 shows that the prevalence of apical diastolic murmurs of MS in patients with MAC ranged from 0% to 25% in different studies (85,113–118,120,121). Table 11 also indicates that MS associated with MAC was diagnosed by Doppler echocardiography in 8% of 51 patients by Labovitz and colleagues (120), in 6% of 100 patients by Aronow and Kronzon (118), and in 8% of 1028 patients by Aronow et al. (114). Figure 7 illustrates MS due to MAC diagnosed by Doppler echocardiography. The reduction of mitral valve orifice in patients with MAC is due to the annular calcium and to decreased mitral excursion and mobility secondary to calcium at the base of the leaflets (118). The commissures are fused in rheumatic MS but are not fused in MS associated with MAC. The mitral leaflet margins in MAC may be thin and mobile, and the posterior mitral leaflet may move normally during diastole. However, Doppler echocardiographic recordings show increased transvalvular flow velocity and prolonged

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Table 11 Prevalence of Apical Diastolic Murmurs of MS and of MS in Patients with MAC Prevalence of MS murmur

Prevalence of MS by Doppler echocardiography

n

%

n

%

Simon and Liu (121) Korn et al. (115) Schott et al. (116)

5/59 3/14 2/14

8 21 14a

Savage et al. (85) Nair et al. (113) Aronow et al. (117) Labovitz et al. (120) Aronow et al. (118) Aronow et al. (114)

2/132 7/104 28/293 0/51 6/100 —

2 7 10 0 6 —

— — — — — — — 4/51 6/100 83/1028

— — — — — — — 8 6 8

a

MAC due to noninflammatory calcific disease. Abbreviations: MS, mitral stenosis; MAC, mitral annular calcium.

Figure 7 Continuous-wave Doppler tracing across a stenotic mitral valve orifice due to mitral annular calcium. Peak diastolic gradient ¼ 12 mmHg. Pressure halftime ¼ 200 milliseconds. Mitral valve area ¼ 1.1 cm2.

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pressure halftime and, therefore, smaller mitral valve orifice in patients with MS, regardless of the etiology. Bacterial Endocarditis Bacterial endocarditis, with a high incidence of Staphylococcus aureus endocarditis, may complicate MAC (82,83). Patients with MAC associated with chronic renal failure are especially at increased risk for developing bacterial endocarditis (116). The calcific mass erodes the endothelium under the mitral valve, which is exposed to transient bacteremia. The avascular nature of the mitral annulus interferes with antibiotics reaching a nidus of bacteria, predisposing to periannular and myocardial abscesses and, consequently, to a poor prognosis (122). Burnside and DeSanctis (122) therefore recommended prophylactic antibiotics to prevent bacterial endocarditis in patients with MAC. Nair and colleagues (113) observed at 4.4-year mean follow-up with no significant difference in incidence of bacterial endocarditis in 99 patients younger than 61 years with MAC compared to a control group of 101 patients. However, Aronow and colleagues (83) demonstrated at 39-month mean follow-up a 3% incidence of bacterial endocarditis in 526 elderly patients with MAC and a 1% incidence of bacterial endocarditis in 450 elderly patients without MAC. On the basis of these data, prophylactic antibiotics should be used to prevent bacterial endocarditis in patients with MAC, according to American Heart Association guidelines (123).

Cardiac Events In a prospective study of 107 patients (8 lost to follow-up) younger than 61 years with MAC and 107 (6 lost to follow-up) age- and sex-matched control subjects, Nair and colleagues (113) demonstrated at 4.4-year mean follow-up that patients with MAC had a higher incidence of new cardiac events than control subjects (Table 12). In a prospective study of 526 elderly patients with MAC and 450 elderly patients without MAC, Aronow and colleagues (83) found at 39-month mean follow-up that the incidence of new cardiac events (myocardial infarction, primary ventricular fibrillation, or sudden cardiac death) was also higher in elderly patients with MAC than in elderly patients without MAC (Table 12). Mitral Valve Replacement Nair and colleagues (124) reported that mitral valve replacement could be accomplished in patients with MAC with morbidity and mortality similar to that in patients without MAC. Following mitral valve replacement, subsequent morbidity and mortality during 4.4-year mean follow-up were also similar in patients with and without MAC. Cerebrovascular Events Although the increased prevalence of AF, MS, MR, left atrial enlargement, and congestive heart failure predisposes patients with MAC to thromboembolic stroke, some investigators consider MAC a marker of other vascular disease causing stroke rather the primary embolic source (125). In a retrospective study of 110 elderly patients with chronic AF, 44 (40%) had documented thromboembolic stroke (126). In this study, the prevalence of MAC was not significantly different in elderly patients with

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Table 12 Incidence of New Cardiac Events in Patients With and Without MAC Cardiac events MAC Follow-up Nair et al. (113) Total cardiac death Sudden cardiac death Congestive heart failure Mitral or aortic valve replacement Aronow et al. (83) cardiac eventsa if: Atrial fibrillation Sinus rhythm All patients

yr

No MAC

n

%

n

%

Relative risk

31/99 12/99 41/99 9/99

31 12 41 9

2/101 1/101 6/101 0/101

2 1 6 0

15.5 12.0 6.8 —

62/90 157/436 219/526

69 36 42

22/41 106/409 128/450

54 26 28

1.3 1.4 1.5

39 mo

a

Myocardial infarction, primary ventricular fibrillation, or sudden cardiac death. Abbreviation: MAC, mitral annular calcium.

Table 13 Incidence of New Cerebrovascular Events in Patients With and Without MAC Cerebrovascular events MAC n

%

n

%

Relative risk

4.4 yr

10/99

10

2/101

2

5.0

8 yr

22/160

14

51/999

5

2.7

45/90 59/436 104/526 10/129

50 14 20 8

14/41 38/409 52/450 5/291

34 9 12 2

1.5 1.6 1.7 4.0

52/101 88/365

51 24

16/49 47/413

33 11

1.5 2.2

8/101 11/365

8 3

3/49 3/413

6 1

1.3 3.0

Follow-up Nair et al. (113) TE cardiovascular events Benjamin et al. (127) stroke Aronow et al. (83) TE stroke if: Atrial fibrillation Sinus rhythm All patients Boston Area Anticoagulation Trial for Atrial Fibrillation (128) ischemia stroke Aronow et al. (129) TE stroke if: 40–100% ECD 0–39% ECD TIA if: 40–100% ECD 0–39% ECD

No MAC

39 mo

2.2 yr

45 mo

Abbreviations: MAC, mitral annular calcium; TE, thromboembolic; ECD, extracranial carotid arterial disease; TIA, cerebral transient ischemic attack.

thromboembolic stroke (80%) or without thromboembolic stroke (65%) (relative risk ¼ 1.2). However, six prospective studies have demonstrated an increased incidence of new cerebrovascular events in patients with MAC than in patients without MAC (Tables 13–15) (83,113,114,127–129) ranging from a relative risk of 1.5 up to 5.0.

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Table 14 Incidence of New Thromboembolic Stroke at 44-Month Mean Follow-Up in Elderly Patients with Chronic Atrial Fibrillation Thromboembolic stroke (%) Atrial Atrial Atrial Atrial

fibrillation, no MAC (n ¼ 85) fibrillation with MS due to MAC (n ¼ 42) fibrillation with MAC and 2–4 þ MR (n ¼ 90) fibrillation with MAC and 0–1 þ MR (n ¼ 93)

(35) (74) (59) (48)

Abbreviation: MAC, mitral annular calcium. Source: From Ref. 114.

Table 15 Incidence of New Thromboembolic Stroke at 44-Month Mean Follow-Up in Elderly Patients With Sinus Rhythm Thromboembolic stroke (%) Sinus Sinus Sinus Sinus

rhythm, no MAC (n ¼ 1035) rhythm with MS due to MAC (n ¼ 41) rhythm with MAC and 2–4 þ MR (n ¼ 134) rhythm with MAC and 0–1 þ MR (n ¼ 625)

9 32 28 24

Abbreviations: MR, mitral regurgitation; MAC, mitral annular calcium. Source: From Ref. 114.

Aronow and colleagues studied the incidence of new thromboembolic stroke at 44-month mean follow-up in 310 unselected elderly patients with chronic AF in a long-term health-care facility (114) (Table 14). MS and the severity of MR were diagnosed by Doppler echocardiography in this study (114). In elderly persons with chronic AF, MAC increased the incidence of new thromboembolic stroke 2.1 times if MS was associated with MAC, 1.7 times if 2–4 þ MR was associated with MAC, and 1.4 times if 0–1 þ MR was present. Table 15 shows the incidence of new thromboembolic stroke at 44-month mean follow-up in 1838 unselected older persons, mean age 81 years, with sinus rhythm, in a long-term health-care facility (114). In elderly persons with sinus rhythm, MAC increased the incidence of new thromboembolic stroke 3.6 times if MS was associated with MAC, 3.1 times if 2–4 þ MR was associated with MAC, and 2.7 times if 0–1 þ MR was present. Using the multivariate Cox regression model, independent risk factors for new thromboembolic stroke in this study were prior stroke (risk ratio ¼ 2.4), MAC (risk ratio ¼ 2.6), AF (risk ratio ¼ 3.0), and male gender (risk ratio ¼ 1.6). There was a higher prevalence of MAC in elderly patients with 40% to 100% ECAD (67% of 150 patients) than in elderly patients with 0% to 39% ECAD (47% of 778 patients) (129). The increased prevalence of significant ECAD contributes to a higher stroke rate. Thrombi of the mitral annulus also contribute to thromboembolic stroke in elderly patients with MAC (130,131). In addition, MAC is associated with aortic atheromatous disease (105), complex intra-aortic debris (132), and thoracic aorta calcium (109), which could contribute to thromboembolic stroke. Some patients with MAC who experienced thromboembolic events also had a mobile component that was associated with the thromboembolic events (133). There was no significant difference in the association of MAC with prior stroke between elderly whites and elderly African-Americans, between elderly whites and elderly Hispanics, and between elderly African-Americans and elderly Hispanics (134).

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Kizer and colleagues (135) from the Strong Heart Study, followed 2723 AmericanIndians without clinical cardiovascular disease and with baseline echocardiograms for seven years. Eighty-six strokes occurred. The presence of MAC but not aortic valve sclerosis was a strong risk factor for incident stroke after extensive adjustment for other predictors. Since patients with MAC and AF or sinus rhythm have a higher incidence of thromboembolic stroke than patients without MAC, antithrombotic therapy should be considered in patients with MAC and no contraindications to antithrombotic therapy. In the Boston Area Anticoagulation Trial for Atrial Fibrillation study, warfarin reduced the incidence of thrombembolic stroke in patients with MAC by about 90% (136,137). Until data from prospective, randomized studies evaluating the efficacy and risk of antithrombotic therapy in patients with MAC are available, patients with MAC associated with either AF, MS, or moderate-to-severe MR should be considered for treatment with warfarin if they have no contraindications to anticoagulant therapy. The international normalised ratio should be maintained between 2.0 and 3.0. The efficacy of antiplatelet therapy in patients with MAC is unknown. REFERENCES 1. Muddassir SM, Pressman GS. Mitral annular calcification as a cause of mitral valve gradients. Int J Cardiol. 2007 Feb 21; [Epub ahead of print] 2. Edwards MB, Taylor KM. A profile of valve replacement surgery in the UK (1986–1997): a study from the UK Heart Valve Registry. J Heart Valve Dis 1999; 8:697–701. 3. Cheitlin MD. Management of Valve Disease in the Elderly. Am J Geriatr Cardiol 1996; 5:65–67. 4. Cannistra LB, Gaasch WH. Appetite-suppressing drugs and valvular heart disease. Cardiol Rev. 1999; 7:356–61. 5. Rothman RB, Baumann MH, Savage JE, et al. Evidence for possible involvement of 5-HT(2B) receptors in the cardiac valvulopathy associated with fenfluramine and other serotonergic medications. Circulation. 2000; 102:2836–2841. 6. Zanettini R, Antonini A, Gatto G, et al. Valvular heart disease and the use of dopamine agonists for Parkinson’s disease. N Engl J Med. 2007; 356:39–46. 7. Cheitlin MD. The timing of surgery in mitral and aortic valve disease. Curr Probl Cardiol 1987; 12:69–149. 8. Goldsmith I, Kumar P, Carter P, et al. Atrial endocardial changes in mitral valve disease: a scanning electron microscopy study. Am Heart J 2000; 140:777–784. 9. Chiang CW, Lo SK, Kuo CT, et al. Noninvasive predictors of systemic embolism in mitral stenosis. An echocardiographic and clinical study of 500 patients. Chest 1994; 106:396–399. 10. Kishan CV, Wongpraparut N, Adeleke K, et al. Ortner’s syndrome in association with mitral valve prolapse. Clin Cardiol 2000; 23:29–295. 11. Otsuji Y, Handschumacher MD, Liel-Cohen N, et al. Mechanism of ischemic mitral regurgitation with segmental left ventricular dysfunction: three-dimensional echocardiographic studies in models of acute and chronic progressive regurgitation. J Am Coll Cardiol 2001; 37:641–648. 12. Cheitlin MD, Byrd RC. Prolapsed mitral valve: the commonest valve disease? Curr Prob Cardiol 1984; 8:1–54. 13. Carabello BA. Progress in mitral and aortic regurgitation. Prog Cardiovasc Dis 2001; 43:457–475. 14. Swinne CJ, Shapiro EP, Lima SD, et al. Age-associated changes in left ventricular diastolic performance during isometric exercise in normal subjects. Am J Cardiol 1992; 69:823–826. 15. Vaitkevicius PV, Fleg JL, Engel JH, et al. Effects of age and aerobic capacity on arterial stiffness in healthy adults. Circulation 1993; 88:1456–1462.

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